Dicarboxylic acid foamable vehicle and pharmaceutical compositions thereof

ABSTRACT

The present invention teaches a foamable pharmaceutical carrier comprising a benefit agent, selected from the group consisting of a dicarboxylic acid and a dicarboxylic acid ester; a stabilizer selected from the group consisting of at least one surface-active agent; at least one polymeric agent and mixtures thereof; a solvent selected from the group consisting of water, a hydrophilic solvent, a hydrophobic solvent, a potent solvent, a polar solvent, a silicone, an emollient, and mixtures thereof, wherein the benefit agent, stabilizer and solvent are selected to provide a composition that is substantially resistant to aging and to phase separation and or can substantially stabilize other active ingredients. The invention further relates to a foamable composition further containing a liquefied hydrocarbon gas propellant.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. patentapplication Ser. No. 15/903,275, filed Feb. 23, 2018, which is acontinuation application of U.S. patent application Ser. No. 13/796,860,filed Mar. 12, 2013, which is a continuation of U.S. patent applicationSer. No. 11/825,406, filed on Jul. 5, 2007, which (1) claims the benefitunder 35 U.S.C. § 119(e) of U.S. Provisional Patent Application No.60/818,634, filed on Jul. 5, 2006, entitled “Dicarboxylic Acid FoamableVehicle and Pharmaceutical Compositions Thereof;” (2) is acontinuation-in-part of U.S. patent application Ser. No. 10/532,618,filed Dec. 22, 2005, which is a 371 of International Patent ApplicationNo. 1603/005527, designating the United States and filed on Oct. 24,2003, which claims the benefit of priority under 35 U.S.C. § 119(e) toU.S. Patent Application No. 60/429,546, filed on Nov. 29, 2002, bothentitled “Cosmetic and Pharmaceutical Foam,” and which claims thebenefit of priority under 35 U.S.C. § 119(a) to Israeli PatentApplication No. 152486, filed Oct. 25, 2002; (3) is acontinuation-in-part of U.S. patent application Ser. No. 10/911,367,filed on Aug. 4, 2004, which claims the benefit of priority under 35U.S.C. § 119(e) to U.S. Patent Application No. 60/492,385, filed on Aug.4, 2003, both entitled “Foam Carrier Containing Amphiphilic CopolymerGelling Agent;” (4) is a continuation-in-part of U.S. patent applicationSer. No. 11/653,205, filed on Jan. 12, 2007, entitled “OleaginousPharmaceutical And Cosmetic Foam,” which is a) a continuation-in-partapplication of U.S. patent application Ser. No. 10/835,505, filed onApr. 28, 2004, which claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Patent Application No. 60/530,015, filed on Dec. 16,2003, and U.S. Patent Application No. 60/492,385, filed on Aug. 4, 2003,and b) a continuation-in-part of U.S. patent application Ser. No.10/911,367, filed on Aug. 4, 2004, which claims the benefit of priorityunder 119(e) to U.S. Patent Application No. 60/492,385, filed on Aug. 4,2003; (5) is a continuation-in-part of U.S. patent application Ser. No.11/717,897, filed on Mar. 13, 2007, entitled “Foamable Compositions,Kits and Methods for Hyperhidrosis;” and (6) is a continuation-in-partof U.S. patent application Ser. No. 11/078,902, filed on Mar. 11, 2005,entitled “Nonsteroidal Immunomodulating Kit and Composition and UsesThereof;” all of which are incorporated herein by reference in theirentirety.

BACKGROUND OF THE INVENTION

This invention relates to foamable pharmaceutical and cosmeticcompositions.

External topical administration is an important route for theadministration of drugs in disease treatment. Many groups of drugs,including, for example, antibiotic, anti-fungal, anti-inflammatory,anesthetic, analgesic, anti-allergic, corticosteroid, retinoid andanti-proliferative medications are preferably administered inhydrophobic media, namely ointment. However, ointments often form animpermeable barrier, so that metabolic products and excreta from thewounds to which they are applied are not easily removed or drained away.Furthermore, it is difficult for the active drug dissolved in thecarrier to pass through the white petrolatum barrier layer into thewound tissue, so the efficacy of the drug is reduced. In addition,ointments and creams often do not create an environment for promotingrespiration of the wound tissue and it is not favorable to the normalrespiration of the skin. An additional disadvantage of petroleumjelly-based products relates to the greasy feeling left following theirtopical application onto the skin, mucosal membranes and wounds.

Foams are considered a more convenient vehicle for topical delivery ofactive agents. There are several types of topical foams, includingaqueous foams, such as commonly available shaving foams; hydroalcoholicfoams, emulsion-based foams, comprising oil and water components, andoleaginous foams, which consist of high oil content. In skin therapy,oil containing foams are preferred, since oil contributes to skinprotection and moisturization, which improve the therapeutic effect ofthe formulation.

Dicarboxylic acids are known to possess therapeutic properties.Dicarboxylic acids, and their mercapto, ester and salt derivatives havebeen used in the treatment of a variety of skin disorders and/orconditions.

Azelaic acid (AZA) is a naturally occurring nine carbon straight chainmolecule with two terminal carboxyl groups. AZA is an anti-keratinizingagent, displaying antiproliferative effects on keratinocytes andmodulating the early and terminal phases of epidermal differentiation.AZA is a competitive inhibitor of the reduction of testosterone todihydrotestosterone, and as such is supposed to reduce the production ofsebum in the sebaceous gland. Furthermore, recent investigations havedemonstrated that AZA and sebacic acid also have anti-bacterial andanti-fungal properties. Structure-activity relationship studies haverevealed that these effects are retained when the dicarboxylic acid hasa backbone of about 6 to about 14 carbons.

Dicarboxylic acid esters are also known to contribute to the skinpenetration of an active agent. Enhancing effects on skin penetration ofmethyl nicotinate have been observed with dibutyl adipate and dioctyladipate. Diisopropyl sebacate also markedly enhances the skinpenetration of the erythromycin. The skin penetration enhancingproperties of mono- or di-esters of dicarboxylic acid, including dibutyladipate, diethyl sebacate, diisopropyl dimerate, diisopropyl adipate,diisopropyl sebacate and dioctyl succinate have been recognized.

There remains an unmet need for improved, easy to use, stableoil-containing foam formulations, containing oils, which effectivelydeliver and/or deposit various benefit agents into and onto the skinand/or other target sites and are relatively non-irritating and thussuitable for use by people having sensitive skin and eyes.

SUMMARY

The present invention relates to aqueous and non aqueous stablecompositions comprising a dicarboxylic acid or ester derivative thereofin which the dicarboxylic acid or ester derivative is a stabilizingemollient and or has a therapeutic effect.

There is provided a pharmaceutical or cosmetic composition comprising:

-   -   a. a beneficially or therapeutically effective concentration of        at least one benefit agent, selected from the group consisting        of        -   i. a dicarboxylic acid; and        -   ii. a dicarboxylic acid ester;    -   b. a stabilizer selected from the group consisting of at least        one surface-active agent; at least one polymeric agent and        mixtures thereof; and    -   c. a solvent selected from the group consisting of water; a        hydrophilic solvent; a hydrophobic solvent; a potent solvent; a        polar solvent, a silicone, an emollient, and mixtures thereof;

wherein the benefit agent is an emollient solvent and or apharmaceutical or cosmetic agent;

wherein the polymeric agent is about 0.01% to about 5% by weight and isselected from the group consisting of a bioadhesive agent, a gellingagent, a film forming agent and a phase change agent;

wherein the benefit agent, stabilizer and solvent are selected toprovide a composition that is substantially resistant to aging and tophase separation and or can substantially stabilize other activeingredients; and

wherein if the composition is contained in a pressurized container andfurther comprises a liquefied hydrocarbon gas propellant at aconcentration of about 3% to about 25% by weight of the totalcomposition it is substantially flowable and provides a foam uponrelease.

There is also provided a foamable composition as described above whereinthe composition is contained in a pressurized container and furthercomprises a liquefied hydrocarbon gas propellant at a concentration ofabout 3% to about 25% by weight of the total composition, issubstantially flowable and provides a foam upon release and wherein thebenefit agent, stabilizer and solvent are selected to generate abreakable foam of good to excellent quality.

There is also provided a therapeutic composition comprising:

-   -   a. a therapeutically effective amount of an active agent;    -   b. a beneficially or therapeutically effective concentration of        at least one benefit agent, selected from the group consisting        of        -   i. a dicarboxylic acid; and        -   ii. a dicarboxylic acid ester;    -   c. a stabilizer selected from the group consisting of at least        one surface-active agent; at least one polymeric agent and        mixtures thereof; and    -   d. a solvent selected from the group consisting of water; a        hydrophilic solvent; a hydrophobic solvent; a potent solvent; a        polar solvent, a silicone, an emollient, and mixtures thereof;

wherein the benefit agent is an emollient solvent and or apharmaceutical or cosmetic agent;

wherein the polymeric agent is about 0.01% to about 5% by weight and isselected from the group consisting of a bioadhesive agent, a gellingagent, a film forming agent and a phase change agent;

wherein the benefit agent, stabilizer and solvent are selected toprovide a composition that is substantially resistant to aging and tophase separation and or can substantially stabilize other activeingredients; and

wherein if the composition is contained in a pressurized container andfurther comprises a liquefied hydrocarbon gas propellant at aconcentration of about 3% to about 25% by weight of the totalcomposition it is substantially flowable and provides a foam uponrelease.

There is also provided a method of treating a disorder of a mammaliansubject, comprising:

administering a foamable therapeutic composition to a target site, thecomposition comprising:

-   -   e. a therapeutically effective amount of an active agent;    -   f. a beneficially or therapeutically effective concentration of        at least one benefit agent, selected from the group consisting        of        -   i. a dicarboxylic acid; and        -   ii. a dicarboxylic acid ester;    -   g. a stabilizer selected from the group consisting of at least        one surface-active agent; at least one polymeric agent and        mixtures thereof.    -   h. a solvent selected from the group consisting of water; a        hydrophilic solvent; a hydrophobic solvent; a potent solvent; a        polar solvent, a silicone, an emollient, and mixtures thereof;

wherein the benefit agent is an emollient solvent and or apharmaceutical or cosmetic agent;

wherein the polymeric agent is about 0.01% to about 5% by weight and isselected from the group consisting of a bioadhesive agent, a gellingagent, a film forming agent and a phase change agent;

wherein the benefit agent, stabilizer and solvent are selected toprovide a composition that is substantially resistant to aging and tophase separation and or can substantially stabilize other activeingredients; and

wherein if the composition is contained in a pressurized container andfurther comprises a liquefied hydrocarbon gas propellant at aconcentration of about 3% to about 25% by weight of the totalcomposition it is substantially flowable and provides a foam uponrelease.

There is also provided a pharmaceutical or cosmetic non aqueouscomposition comprising:

-   -   a. a beneficially or therapeutically effective concentration of        at least one benefit agent, selected from the group consisting        of        -   i. a dicarboxylic acid; and        -   ii. a dicarboxylic acid ester;    -   b. a stabilizer selected from the group consisting of at least        one surface-active agent; at least one polymeric agent and        mixtures thereof; and    -   c. a solvent selected from the group consisting of a hydrophilic        solvent; a hydrophobic solvent; a potent solvent; a polar        solvent, a silicone, an emollient, and mixtures thereof;

wherein the benefit agent is an emollient solvent and or apharmaceutical or cosmetic agent;

wherein the polymeric agent is about 0.01% to about 5% by weight and isselected from the group consisting of a bioadhesive agent, a gellingagent, a film forming agent and a phase change agent;

wherein the benefit agent, stabilizer and solvent are selected toprovide a composition that is substantially resistant to aging and tophase separation and or can substantially stabilize other activeingredients; and

wherein if the composition is contained in a pressurized container andfurther comprises a liquefied hydrocarbon gas propellant at aconcentration of about 3% to about 25% by weight of the totalcomposition it is substantially flowable and provides a foam uponrelease.

There is also provided a therapeutic composition comprising:

-   -   a. a therapeutically effective amount of an active agent wherein        the active agent is substantially insoluble in water;    -   b. a beneficially or therapeutically effective concentration of        at least one benefit agent, comprising a dicarboxylic acid ester        in which the active agent is substantially soluble;    -   c. a stabilizer selected from the group consisting of at least        one surface-active agent; at least one polymeric agent and        mixtures thereof; and    -   d. a solvent selected from the group consisting of water; a        hydrophilic solvent; a hydrophobic solvent; a potent solvent; a        polar solvent, a silicone, an emollient, and mixtures thereof;

wherein the benefit agent is an emollient solvent and or apharmaceutical or cosmetic agent;

wherein the polymeric agent is about 0.01% to about 5% by weight and isselected from the group consisting of a bioadhesive agent, a gellingagent, a film forming agent and a phase change agent;

wherein the benefit agent, stabilizer and solvent are selected toprovide a composition that is substantially resistant to aging and tophase separation and or can substantially stabilize other activeingredients; and

wherein if the composition is contained in a pressurized container andfurther comprises a liquefied hydrocarbon gas propellant at aconcentration of about 3% to about 25% by weight of the totalcomposition it is substantially flowable and provides a foam uponrelease.

There is also provided a foamable composition comprising:

-   -   a. a liquid dicarboxylic acid ester, said ester having emollient        properties;    -   b. a stabilizer selected from the group consisting of at least        one surface-active agent; at least one polymeric agent and        mixtures thereof.    -   c. an active agent, said active agent soluble in or having        enhanced penetration due to the dicarboxylic acid;    -   wherein the composition is contained in a pressurized container        and further comprises a liquefied hydrocarbon gas propellant at        a concentration of about 3% to about 25% by weight of the total        composition it is substantially flowable and provides a foam        upon release.

There is also provided a foamable composition comprising:

-   -   a. a beneficially or therapeutically effective concentration of        at least one benefit agent, selected from the group consisting        of        -   i. a dicarboxylic acid; and        -   ii. a dicarboxylic acid ester;    -   b. an ester-based or ether-based surfactant;    -   c. a solvent selected from the group consisting of a hydrophilic        solvent; a hydrophobic solvent; a potent solvent; a polar        solvent, a silicone, an emollient, and mixtures thereof;    -   wherein the composition is substantially free of polymeric        material, and    -   wherein the composition is contained in a pressurized container        and further comprises a liquefied hydrocarbon gas propellant at        a concentration of about 3% to about 25% by weight of the total        composition it is substantially flowable and provides a foam        upon release.

There is also provided a pharmaceutical or cosmetic compositioncomprising:

-   -   a. a beneficially or therapeutically effective concentration of        at least one benefit agent, selected from the group consisting        of        -   i. a dicarboxylic acid; and        -   ii. a dicarboxylic acid ester;    -   b. a stabilizer selected from the group consisting of at least        one surface-active agent; at least one polymeric agent and        mixtures thereof; and    -   c. a solvent selected from the group consisting of a hydrophilic        solvent; a hydrophobic solvent; a potent solvent; a polar        solvent, a silicone, an emollient, and mixtures thereof;

wherein the composition is substantially free of water; and

wherein the composition is contained in a pressurized container andfurther comprises a liquefied hydrocarbon gas propellant at aconcentration of about 3% to about 25% by weight of the totalcomposition it is substantially flowable and provides a foam uponrelease.

There is also provided a formulation of any of the compositionsdescribed above wherein the composition is in a non foam state.

There is also provided a formulation of any of the compositionsdescribed above for use in the manufacture of a medicament.

DETAILED DESCRIPTION

The present invention relates to a composition comprising a benefitagent, selected from the group consisting of (i) a dicarboxylic acid;and (ii) a dicarboxylic acid ester for use as vehicle composition.

According to one or more embodiments of the present invention, thecomposition includes:

-   -   a. a benefit agent, selected from the group consisting of        -   i. a dicarboxylic acid; and        -   ii. a dicarboxylic acid ester;    -   b. a surface-active agent;    -   c. about 0.01% to about 5% by weight of at least one polymeric        agent selected from the group consisting of a bioadhesive agent,        a gelling agent, a film forming agent and a phase change agent;        and    -   d. water.

The present invention further relates to a foamable compositionincluding:

-   -   a. a benefit agent, selected from the group consisting of        -   i. a dicarboxylic acid; and        -   ii. a dicarboxylic acid ester;    -   b. a surface-active agent;    -   c. about 0.01% to about 5% by weight of at least one polymeric        agent selected from the group consisting of a bioadhesive agent,        a gelling agent, a film forming agent and a phase change agent;    -   d. water; and    -   e. liquefied hydrocarbon gas propellant at a concentration of        about 3% to about 25% by weight of the total composition.

In one or more embodiments there is provided a pharmaceutical orcosmetic composition comprising:

-   -   a. a beneficially or therapeutically effective concentration of        at least one benefit agent, selected from the group consisting        of        -   i. a dicarboxylic acid; and        -   ii. a dicarboxylic acid ester;    -   b. a stabilizer selected from the group consisting of at least        one surface-active agent; at least one polymeric agent and        mixtures thereof.    -   c. a solvent selected from the group consisting of water; a        hydrophilic solvent; a hydrophobic solvent; a potent solvent; a        polar solvent, a silicone, an emollient, and mixtures thereof;

wherein the benefit agent is an emollient solvent and or apharmaceutical or cosmetic agent

wherein the polymeric agent is about 0.01% to about 5% by weight and isselected from the group consisting of a bioadhesive agent, a gellingagent, a film forming agent and a phase change agent;

wherein the benefit agent, stabilizer and solvent are selected toprovide a composition that is substantially resistant to aging and tophase separation and or can substantially stabilize other activeingredients;

wherein if the composition is contained in a pressurized container andfurther comprises a liquefied hydrocarbon gas propellant at aconcentration of about 3% to about 25% by weight of the totalcomposition it is substantially flowable and provides a foam uponrelease.

In one or more embodiments there is provided a foamable compositionwhich produces a foam upon release and wherein the benefit agent,stabilizer and solvent are selected to generate a breakable foam of goodto excellent quality.

In one or more embodiments there is provided a composition wherein thebenefit agent, stabilizer and solvent are selected to generate anemulsion that is substantially resistant to phase reversal.

In one or more embodiments there is provided a composition wherein, thebenefit agent, stabilizer and solvent are selected to generate a singlephase.

In one or more embodiments there is provided a composition wherein, thebenefit agent, stabilizer and solvent are selected to generate asubstantially uniform suspension of benefit agent crystals.

In one or more embodiments there is provided a composition, wherein thebreakable foam comprises micro or nano particles, crystals or bodies.

In one or more embodiments there is provided a composition, which issubstantially resistant to one or more Freeze-Thaw cycles (FTC).

In one or more embodiments there is provided a composition wherein thesurface-active agent is a solid, a liquid or a mixture thereof.

In one or more embodiments there is provided a composition wherein thesurface active agent is selected from the group consisting of apolysorbate, polyoxyethylene (20) sorbitan monostearate, polyoxyethylene(20) sorbitan monooleate, a polyoxyethylene fatty acid ester, Myrj 45,Myrj 49, Myrj 52 and Myrj 59; a polyoxyethylene alkylyl ether,polyoxyethylene cetyl ether, polyoxyethylene palmityl ether,polyethylene oxide hexadecyl ether, polyethylene glycol cetyl ether,brij 38, brij 52, brij 56 and brij W1, a sucrose ester, a partial esterof sorbitol, sorbitan monolaurate, sorbitan monolaurate a monoglyceride,a diglyceride, isoceteth-20, a sucrose ester, or selected from the groupconsisting of steareth 2, glyceryl monostearate/PEG 100 stearate,Glyceryl Stearate, Steareth-21, peg 40 stearate, polysorbate 60,polysorbate 80, sorbitan stearate, laureth 4, Sorbitan monooleate,ceteareth 20, steareth 20, ceteth 20, Macrogol Cetostearyl Ether, ceteth2, PEG-30 Dipolyhydroxystearate, sucrose distearate, polyoxyethylene(100) stearate, PEG 100 stearate, laureth 4, cetomacrogol ether,Cetearyl alcohol, Cetearyl glucoside, Oleyl alcohol, Steareth-2,Diisopropyl adipate, Capric/caprilic triglicerides, Polysorbate 20;Montanov 68 (CETEARYL ALCOHOL (and) CETEARYL GLUCOSIDE.), Sharonmix 824(a liquid blend of methyl paraben, ethyl paraben and propyl paraben—inphenoxyethanol), Simusol 165 (Glyceryl stearate and PEG-100 stearate).Methyl glucose sequistearate, Peg 30 dipolyhydroxystearate, sucrosestearic acid esters, sorbitan laureth, sorbitan stearate and mixturesthereof.

In one or more embodiments there is provided a composition wherein thesurface active agent comprises at least one ester based surfactant or atleast one ether based surfactant.

In one or more embodiments there is provided a composition wherein thesurface active agent is reduced about in proportion to the increase indicarboxylic ester.

In one or more embodiments there is provided a composition wherein thestabilizer is not a polymeric agent.

In one or more embodiments there is provided a composition wherein thesurface active agent comprises a non-ionic surfactant that does notcontain a polyoxyethylene (POE) moiety.

In one or more embodiments there is provided a composition wherein thesurface active agent is selected from the group consisting of anon-ethoxylated sorbitan ester, a glycerol fatty acid ester, a sucroseester and an alkyl polyglycoside or is selected from the groupconsisting of sorbitan monopalmitate, sorbitan monostearate, sorbitantristearate, sorbitan monooleate, sorbitan trioleate, sorbitanmonolaurate, sorbitan sesquioleate, glycerol monostearate, glycerolmonooleate, sucrose stearate, sucrose distearate, sucrose palmitatesucrose laurate and lauryl diglucoside.

In one or more embodiments there is provided a composition wherein thepolymeric agent is selected from the group consisting of carbopol 934,pemulen TR2, klucel EF, xanthan gum, methocel A4M, and carboxy methylcellulose or selected from the group consisting of locust bean gum,sodium alginate, sodium caseinate, egg albumin, gelatin agar,carrageenin gum, sodium alginate, xanthan gum, quince seed extract,tragacanth gum, guar gum, cationic guars, hydroxypropyl guar gum,starch, an amine-bearing polymer, chitosan, alginic acid, hyaluronicacid, a chemically modified starch, a carboxyvinyl polymer,polyvinylpyrrolidone, polyvinyl alcohol, a polyacrylic acid polymer, apolymethacrylic acid polymer, polyvinyl acetate, a polyvinyl chloridepolymer, a polyvinylidene chloride polymer, methylcellulose,hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxy propylmethyl cellulose, methylhydroxyethylcellulose,methylhydroxypropylcellulose, hydroxyethylcarboxymethylcellulose,carboxymethyl cellulose, carboxymethylcellulosecarboxymethylhydroxyethylcellulose, a cationic cellulose aluminum starchoctenylsuccinate (ASOS), PEG 1000, PEG 4000, PEG 6000 and PEG 8000.

In one or more embodiments there is provided a composition wherein thepolymeric agent is a derivatized polymer.

In one or more embodiments there is provided a composition wherein thederivatized polymer is a polymeric emulsifier.

In one or more embodiments there is provided a composition wherein thebenefit agent is selected from the group consisting of diisopropyladipate, dimethyl sebacate, dioctyl malate, diethyl sebacate, azelaicacid and TU-2100.

In one or more embodiments there is provided a composition wherein,further comprising an additional active agent.

In one or more embodiments there is provided a composition wherein thedicarboxylic acid has the molecular formula HOOC—(CH₂)_(n)—COOH; andwherein n is in the range between 0 and 32.

In one or more embodiments there is provided a composition wherein n isin the range between 4 and 10.

In one or more embodiments there is provided a composition wherein thedicarboxylic acid is selected from the group consisting of oxalic acid,malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid,suberic acid, azelaic acid, sebacic acid and dodecanedioic acid, maleicacid and fumaric acid.

In one or more embodiments there is provided a composition wherein thedicarboxylic acid is selected from the group consisting of adipic acid,azelaic acid and sebacic acid.

In one or more embodiments there is provided a composition whereinfurther containing a foam adjuvant selected from the group consisting ofa fatty alcohol having 15 or more carbons in their carbon chain; a fattyacid having 16 or more carbons in their carbon chain; fatty alcohols,derived from beeswax and including a mixture of alcohols, a majority ofwhich has at least 20 carbon atoms in their carbon chain; a fattyalcohol having at least one double bond; a fatty acid having at leastone double bond; a branched fatty alcohol; a branched fatty acid and afatty acid substituted with a hydroxyl group.

In one or more embodiments there is provided a composition whereinfurther containing at least one organic carrier selected from the groupconsisting of a hydrophobic organic carrier, an emollient and mixturesthereof, at a concentration of about 2% to about 50% by weight.

In one or more embodiments there is provided a composition wherein thedicarboxylic acid or dicarboxylic acid ester is in a concentrationbetween about 0.1% and about 60%.

In one or more embodiments there is provided a composition wherein thedicarboxylic acid is azelaic acid, and wherein the concentration ofazelaic acid is between 5% and 25%.

In one or more embodiments there is provided a composition wherein thepH of the composition is below the first pKa of the dicarboxylic acid.

In one or more embodiments there is provided a composition wherein thepH of the composition is between the first and second pKa of thedicarboxylic acid.

In one or more embodiments there is provided a composition wherein thepH of the composition is above the second pKa of the dicarboxylic acid.

In one or more embodiments there is provided a composition wherein thedicarboxylic acid is azelaic acid the pH of the composition is below5.3.

In one or more embodiments there is provided a composition wherein thedicarboxylic acid is azelaic acid the pH of the composition is betweenabout 4.5 and about 5.3.

In one or more embodiments there is provided a composition wherein thedicarboxylic acid ester is selected from the group consisting of a monoester of said dicarboxylic acid, and a diester of the dicarboxylic acid.

In one or more embodiments there is provided a composition wherein thealcohol moiety of the dicarboxylic acid ester is selected from the groupconsisting of an alkyl alcohol, an aryl alcohol, methyl alcohol, ethylalcohol, propyl alcohol, isopropyl alcohol, butyl alcohol, isobutylalcohol, t-butyl alcohol, pentyl alcohol, hexyl alcohol, octyl alcohol,decyl alcohol, capryl alcohol, phenol and benzyl alcohol.

In one or more embodiments there is provided a composition wherein thealcohol moiety of the dicarboxylic acid ester is a biologically activealcohol.

In one or more embodiments there is provided a composition wherein thebiologically active alcohol is selected from the group consisting of ahydroxyalkylbenzoate, salicylic acid, a dihydroxybenzene,hydroxytoluene, an alpha-hydroxy acid, retinol, a vitamin A derivative,a steroid, vitamin E, a vitamin E derivative, vitamin D and a vitamin Dderivative.

In one or more embodiments there is provided a composition wherein thedicarboxylic acid ester is selected from the group consisting ofdiisobutyl adipate, diisopropyl adipate, diisopropyl sebacate,diisosteary dimer dilinoleate, diisostearyl fumerate, diisopropyldimerate, diethyl adipate, diethyl sebacate, diethylhexyl adipate,diethylhexyl malate, dioctyl malate, diethyl succinate, and dioctylsebacate.

In one or more embodiments there is provided a composition wherein thedicarboxylic acid ester is diisopropyl adipate, in an amount from about0.1% to about 60%

In one or more embodiments there is provided a composition wherein theorganic carrier is selected from the group consisting of mineral oil,triglycerides, medium chain triglyceride (MCT) oil, capric/caprylictriglyceride, alkyl esters of fatty acids such as isopropyl palmitate,isopropyl myristate, isopropyl isostearate, poly propylene glycol15-stearly ether, octyl palmitate, cetyl lactate, cetyl ricinoleate,tocopheryl acetate, acetylated lanolin alcohol, cetyl acetate, phenyltrimethicone, glyceryl oleate, tocopheryl linoleate, wheat germglycerides, arachidyl propionate, myristyl lactate, decyl oleate,ricinoleate, isopropyl lanolate, pentaerythrityl tetrastearate,neopentylglycol dicaprylate/dicaprate, isononyl isononanoate,isotridecyl isononanoate, myristyl myristate, triisocetyl citrate, octyldodecanol, maleated soybean oil, unsaturated or polyunsaturated oils,such as olive oil, corn oil, soybean oil, canola oil, cottonseed oil,coconut oil, sesame oil, sunflower oil, borage seed oil, syzigiumaromaticum oil, hempseed oil, herring oil, cod-liver oil, salmon oil,flaxseed oil, wheat germ oil, evening primrose oils; essential oils; andsilicone oils, such as dimethicone, cyclomethicone, polyalkyl siloxane,polyaryl siloxane, polyalkylaryl siloxane, a polyether siloxanecopolymer and a poly(dimethylsiloxane)-(diphenyl-siloxane) copolymer.

In one or more embodiments there is provided a composition wherein theorganic carrier comprises a polypropylene glycol alkyl ether.

In one or more embodiments there is provided a composition furthercontaining at least one polar solvent.

In one or more embodiments there is provided a composition wherein thepolar solvent is selected from the group consisting of dimethylisosorbide, glycerol, propylene glycol, hexylene glycol, diethyleneglycol, propylene glycol n-alkanols, terpenes, di-terpenes,tri-terpenes, limonene, terpene-ol, 1-menthol, dioxolane, ethyleneglycol, other glycols, oleyl alcohol, alpha-hydroxy acids, such aslactic acid and glycolic acid, sulfoxides, such as dimethylsulfoxide(DMSO), dimethylformanide, methyl dodecyl sulfoxide, dimethylacetamide,azone (1-dodecylazacycloheptan-2-one), 2-(n-nonyl)-1,3-dioxolane,alkanols, such as dialkylamino acetates, and admixtures thereof.

In one or more embodiments there is provided a composition wherein theorganic carrier is capric/caprylic triglyceride and wherein thedicarboxylic acid is azelaic acid.

In one or more embodiments there is provided a composition wherein thepolar solvent is selected from the group consisting of dimethylisosorbide, glycerol, propylene glycol, hexylene glycol, terpene-ol,oleyl alcohol, lactic acid and glycolic acid wherein the dicarboxylicacid is azelaic acid.

In one or more embodiments there is provided a composition wherein theorganic carrier is capric/caprylic triglyceride.

In one or more embodiments there is provided a composition wherein theorganic solvent comprises at least one organic carrier, selected fromthe group capric/caprylic triglyceride, a polypropylene glycol alkylether an ester of a fatty acid and mineral oil and wherein thedicarboxylic acid ester is diisopropyl adipate.

In one or more embodiments there is provided a composition furthercomprising a polar solvent, selected from the group consisting ofdimethyl isosorbide, glycerol, propylene glycol, hexylene glycol,terpene-ol, oleyl alcohol, lactic acid and glycolic acid.

In one or more embodiments there is provided a composition wherein thebenefit agent, stabilizer and solvent are selected to generate anemulsion that can produce a substantially strong and closed packedbarrier between the oil and the water phases whilst maintaining a fluidconstitution

In one or more embodiments there is provided a composition furthercomprising an additional component selected from the group consisting ofa modulating agent, a polar solvent, an anti perspirant, an anti-staticagent, a buffering agent, a bulking agent, a chelating agent, acolorant, a conditioner, a deodorant, a diluent, a dye, an emollient,fragrance, a humectant, an occlusive agent, a penetration enhancer, aperfuming agent, a permeation enhancer, a pH-adjusting agent, apreservative, a skin penetration enhancer, a sunscreen, a sun blockingagent, a sunless tanning agent, and a vitamin.

In one or more embodiments there is provided a composition wherein theorganic carrier is selected from the group consisting of PPG 15-stearylether, isopropyl myristate and medium chain triglyceride oil andcapric/caprylic triglyceride and the benefit agent is a solid at ambienttemperature.

In one or more embodiments there is provided a therapeutic compositioncomprising therapeutically effective amount of an active agent; and abeneficially or therapeutically effective concentration of at least onebenefit agent, selected from the group consisting of:

i. a dicarboxylic acid; and

ii. a dicarboxylic acid ester

wherein the active agent is selected from the group consisting of activeherbal extracts, acaricides, age spot and keratose removing agents,allergen, analgesics, local anesthetics, antiacne agents, antiallergicagents, antiaging agents, antibacterials, antibiotics, antiburn agents,anticancer agents, antidandruff agents, antidepressants, antidermatitisagents, antiedemics, antihistamines, antihelminths, antihyperkeratolyteagents, antiinflammatory agents, antiirritants, antilipemics,antimicrobials, antimycotics, antiproliferative agents, antioxidants,anti-wrinkle agents, antipruritics, antipsoriatic agents, antirosaceaagents antiseborrheic agents, antiseptic, antiswelling agents, antiviralagents, antiyeast agents, astringents, topical cardiovascular agents,chemotherapeutic agents, corticosteroids, dicarboxylic acids,disinfectants, fungicides, hair growth regulators, hormones, hydroxyacids, immunosuppressants, immunoregulating agents, insecticides, insectrepellents, keratolytic agents, lactams, metals, metal oxides,mitocides, neuropeptides, non-steroidal anti-inflammatory agents,oxidizing agents, pediculicides, photodynamic therapy agents, retinoids,sanatives, scabicides, self tanning agents, skin whitening agents,vasoconstrictors, vasodilators, vitamins, vitamin D derivatives, woundhealing agents and wart removers.

In one or more embodiments there is provided a foamable therapeuticcomposition wherein the dicarboxylic acid ester is present in thecomposition in an amount sufficient to solubilize the active agent.

In one or more embodiments there is provided a foamable therapeuticcomposition wherein the active agent is a steroid.

In one or more embodiments there is provided a foamable therapeuticcomposition wherein the steroid is selected from the group consisting ofbydrocortisone, hydroxyltriamcinolone, alpha-methyl dexamethasone,dexamethasone-phosphate, beclomethsone dipropionate, clobetasolvalemate, desonide, desoxymethasone, desoxycorticosterone acetate,dexamethasone, dichlorisone, diflorasone diacetate, diflucortolonevalerate, fluadrenolone, fluclorolone acetonide, fludrocortisone,flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortinebutylester, fluocortolone, fluprednidene (fluprednylidene) acetate,flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisonebutyrate, methylprednisolone, triamcinolone acetonide, cortisone,cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate,fluradrenolone acetonide, medrysone, amcinafel, amcinafide,betamethasone and the balance of its esters, chloroprednisone,chlorprednisone acetate, clocortelone, clescinolone, dichlorisone,difluprednate, flucloronide, flunisolide, fluoromethalone, fluperolone,fluprednisolone, hydrocortisone valerate, hydrocortisonecyclopentylpropionate, hydrocortmate, mepreddisone, paramethasone,prednisolone, prednisone, beclomethasone dipropionate, triamcinolone.

In one or more embodiments there is provided a foamable therapeuticcomposition wherein the active agent is an immunomodulator.

In one or more embodiments there is provided a foamable therapeuticcomposition, wherein the immunomodulator is selected from the groupconsisting of a cyclic peptides, cyclosporine, tacrolimus, tresperimus,pimecrolimus, sirolimus, verolimus, laflunimus, laquinimod andimiquimod.

In one or more embodiments there is provided a foamable therapeuticcomposition, wherein the dicarboxylic acid ester is present in thecomposition in an amount sufficient to solubilize the immunomodulator.

In one or more embodiments there is provided a foamable therapeuticcomposition, wherein the dicarboxylic acid ester is diisopropyl adipate.

In one or more embodiments there is provided a composition wherein thesurface active agent comprises a non-ionic surfactant that does notcontain a polyoxyethylene (POE) moiety.

In one or more embodiments there is provided a composition wherein thesurface active agent is selected from the group consisting of anon-ethoxylated sorbitan ester, a glycerol fatty acid ester, a sucroseester and an alkyl polyglycoside or is selected from the groupconsisting of sorbitan monopalmitate, sorbitan monostearate, sorbitantristearate, sorbitan monooleate, sorbitan trioleate, sorbitanmonolaurate, sorbitan sesquioleate, glycerol monostearate, glycerolmonooleate, sucrose stearate, sucrose distearate, sucrose palmitatesucrose laurate and lauryl diglucoside.

In one or more embodiments there is provided a composition wherein thedicarboxylic acid is azelaic acid.

In one or more embodiments there is provided a composition wherein thedicarboxylic acid is azelaic acid and further comprising an organicsolvent comprising capric/caprylic triglyceride.

In one or more embodiments there is provided a composition wherein thedicarboxylic acid is azelaic acid and further comprising an organicsolvent comprising capric/caprylic triglyceride and further comprisingat least one polar carrier, selected from the group consisting ofdimethyl isosorbide, glycerol, propylene glycol, hexylene glycol,terpene-ol, oleyl alcohol, lactic acid and glycolic acid.

In one or more embodiments there is provided a method of treating adisorder of a mammalian subject, comprising:

administering a foamable therapeutic composition to a target site, thecomposition comprising a therapeutically effective amount of an activeagent; and a beneficially or therapeutically effective concentration ofat least one benefit agent, selected from the group consisting of

-   -   i. a dicarboxylic acid; and    -   ii. a dicarboxylic acid ester;        wherein the target site is selected from the group consisting of        the skin, a body cavity, a mucosal surface, the nose, the mouth,        the eye, the ear canal, the respiratory system, the vagina and        the rectum.

In one or more embodiments there is provided a method of treating adisorder of a mammalian subject, wherein the disorder is selected fromthe group consisting of dermatological pain, dermatologicalinflammation, acne, acne vulgaris, inflammatory acne, non-inflammatoryacne, acne fulminans, nodular papulopustular acne, acne conglobata,dermatitis, bacterial skin infections, fungal skin infections, viralskin infections, parasitic skin infections, skin neoplasia, skinneoplasms, pruritis, cellulitis, acute lymphangitis, lymphadenitis,erysipelas, cutaneous abscesses, necrotizing subcutaneous infections,scalded skin syndrome, folliculitis, furuncles, hidradenitissuppurativa, carbuncles, paronychial infections, rashes, erythrasma,impetigo, ecthyma, yeast skin infections, warts, molluscum contagiosum,trauma or injury to the skin, post-operative or post-surgical skinconditions, scabies, pediculosis, creeping eruption, eczemas, psoriasis,pityriasis rosea, lichen planus, pityriasis rubra pilaris, edematous,erythema multiforme, erythema nodosum, granuloma annulare, epidermalnecrolysis, sunburn, photosensitivity, pemphigus, bullous pemphigoid,dermatitis herpetiformis, keratosis pilaris, callouses, corns,ichthyosis, skin ulcers, ischemic necrosis, miliaria, hyperhidrosis,moles, Kaposi's sarcoma, melanoma, malignant melanoma, basal cellcarcinoma, squamous cell carcinoma, poison ivy, poison oak, contactdermatitis, atopic dermatitis, rosacea, purpura, moniliasis,candidiasis, baldness, alopecia, Behcet's syndrome, cholesteatoma,Dercum disease, ectodermal dysplasia, gustatory sweating, nail patellasyndrome, lupus, hives, hair loss, Hailey-Hailey disease, chemical orthermal skin burns, scleroderma, aging skin, wrinkles, sun spots,necrotizing fasciitis, necrotizing myositis, gangrene, scarring, andvitiligo; and wherein the active agent is suitable for treating saiddisorderm or is selected from the group consisting of chlamydiainfection, gonorrhea infection, hepatitis B, herpes, HIV/AIDS, humanpapillomavirus (HPV), genital warts, bacterial vaginosis, candidiasis,chancroid, granuloma Inguinale, lymphogranuloma venereum, mucopurulentcervicitis (MPC), molluscum contagiosum, nongonococcal urethritis (NGU),trichomoniasis, vulvar disorders, vulvodynia, vulvar pain, yeastinfection, vulvar dystrophy, vulvar intraepithelial neoplasia (VIN),contact dermatitis, pelvic inflammation, endometritis, salpingitis,oophoritis, genital cancer, cancer of the cervix, cancer of the vulva,cancer of the vagina, vaginal dryness, dyspareunia, anal and rectaldisease, anal abscess/fistula, anal cancer, anal fissure, anal warts,Crohn's disease, hemorrhoids, anal itch, pruritus ani, fecalincontinence, constipation, polyps of the colon and rectum; and whereinthe active agent is suitable for treating said disorder.

In one or more embodiments there is provided a method of treating adisorder of a mammalian subject, wherein the disorder is adermatological disorder, which can be treated by a dicarboxylic acid ordicarboxylic acid ester.

In one or more embodiments there is provided a method of treating adisorder of a mammalian subject, wherein the disorder is adermatological disorder, which can be treated by a topical steroid, animmunomodulator or an anti-infective agent.

In one or more embodiments there is provided a method of treating adisorder of a mammalian subject, wherein the disorder is selected fromatopic dermatitis and psoriasis; and the active agent is selected from(i) steroid; and (ii) a combination of steroid and an additionalnon-steroidal active agent.

In one or more embodiments there is provided a method of treating adisorder of a mammalian subject, wherein the disorder is selected frompsoriasis and atopic dermatitis and the active agent comprises animmunomodulator.

In one or more embodiments there is provided a therapeutic compositioncomprising: a therapeutically effective amount of an active agentwherein the active agent is substantially insoluble in water; and abeneficially or therapeutically effective concentration of at least onebenefit agent, comprising a dicarboxylic acid ester in which the activeagent is substantially soluble; wherein the benefit agent, stabilizerand solvent are selected to generate an emulsion that can produce asubstantially strong and closed packed barrier between the oil and thewater phases whilst maintaining a fluid constitution.

In one or more embodiments there is provided a foamable compositioncomprising: a liquid dicarboxylic acid ester, said ester havingemollient properties; a stabilizer selected from the group consisting ofat least one surface-active agent; at least one polymeric agent andmixtures thereof, an active agent, said active agent soluble in orhaving enhanced penetration due to the dicarboxylic acid; wherein thecomposition is contained in a pressurized container and furthercomprises a liquefied hydrocarbon gas propellant at a concentration ofabout 3% to about 25% by weight of the total composition it issubstantially flowable and provides a foam upon release

In one or more embodiments the stabilizer comprises a ether-based orester-based surfactant.

In one or more embodiments the stabilizer comprises an alkyl-derivatizedpolymer having polymeric emulsifying properties.

In one or more embodiments the composition is an oil in water emulsion.

In one or more embodiments the dicarboxylic acid ester comprises aboutor more than 50 wt % of the composition.

In one or more embodiments the active agent is otherwise insoluble orunstable, but is solubilized or stabilized by DCA.

In one or more embodiments the composition is substantially free ofwater In one or more embodiments the composition is in a non foam state.

In one or more embodiments there is provided a pharmaceutical orcosmetic composition comprising:

-   -   a. a benefit agent, selected from the group consisting of        -   i. a dicarboxylic acid; and        -   ii. a dicarboxylic acid ester;    -   b. a surface-active agent;    -   c. about 0.01% to about 5% by weight of at least one polymeric        agent selected from the group consisting of a bioadhesive agent,        a gelling agent, a film forming agent and a phase change agent;        and    -   d. water.

All % values are provided on a weight (w/w) basis.

Dicarboxylic Acid and Esters Thereof

In an embodiment of the present invention, the organic carrier comprisesan ester of a dicarboxylic acid. In the context of the presentinvention, a dicarboxylic acid is an organic material, having twocarboxylic acid moieties on its carbon atom skeleton. They have thegeneral molecular formula HOOC—(CH₂)_(n)—COOH.

Non limiting examples of some elementary dicarboxylic acids (DCA's) aresuccinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid,azelaic acid, sebacic acid, phthalic acid, isophthalic acid,terephthalic acid.

In an embodiment of the present invention, the dicarboxylic acid is ashort-chain dicarboxylic acid. The simplest Short-chain dicarboxylicacid are oxalic acid (n=0), malonic acid (n=1), succinic acid (n=2) andglutaric acid (n=3).

Additional members of dicarboxylic acid group are derived from naturalproducts or from synthesis, having “n” value from 4 up to 21. In one ormore embodiments of the present invention, the dicarboxylic acid isselected from the group consisting of adipic acid (hexanedioic acid;n=4), pimelic acid (heptanedioic acid; n=5), suberic acid (octanedioicacid; n=6), azelaic acid (nonanedioic acid; n=7), sebacic acid(decanedioic acid; n=8) and dodecanedioic acid (n=10).

In an additional embodiment, the dicarboxylic acid contains 10 to 32carbon atoms in their carbon atom skeleton, such as brassylic acid(n=11), thapsic acid (n=14), 14-methylnonacosanedioic acid (C29) and14,15-dimethyltriacontanedioic acid (C30).

The carbon atom skeleton of the dicarboxylic acid can be saturated orunsaturated, such as in the case of maleic acid and fumaric acid.

In general terms non-esterified dicarboxylic acids are usually solid atambient temperature. Non limiting examples of solid DCA's are oxalic,malonic glutaric, sebacic, phthalic and azaleic acid. Similarly, ingeneral terms DCA's with short carbon chain skeleton are water soluble,such as oxalic, malonic, and succinic acid. Longer chain DCA's likeadipic acid and having up to 10 carbon atoms in the carbon chain areslightly soluble in water. Also non “simple” DCA's are generally solidat ambient temperature, insoluble in water, and are usually more oilsoluble than their parent DCA's

An ester of a dicarboxylic acid is a chemical compound produced by thereaction between a dicarboxylic acid and at least one alcohol, with theelimination of a molecule of water. The reaction of a dicarboxylic acidwith one alcohol molecule results in a mono ester of a dicarboxylicacid. The reaction of a dicarboxylic acid with two alcohol moleculesresults in a diester of the dicarboxylic acid.

DCA esters are typically hydrophobic and generally insoluble in water.Most simple esters of DCA are liquid. By simple it is meant that thealcohol moiety linked to the DCA is a straight or branched alkyl chain.Examples of liquid simple diesters are dimethyl phthalate, diethylphthalate, dibutyl phthalate, diethyl sebacate, dibutyl sebacate, anddiisopropyl adipate. Aromatic diesters of pthalic, isopthalic andtherephalic acids are in the range of slightly soluble to insoluble.

The alcohol molecule, to be linked to the dicarboxylic acid, can beselected from the group of an alkyl an aryl alcohol. Exemplary alcohol,suitable according to the present invention include methyl alcohol,ethyl alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol,isobutyl alcohol, t-butyl alcohol, pentyl alcohol, hexyl alcohol, octylalcohol, decyl alcohol, capryl alcohol, phenol, benzyl alcohol and thelike.

In one or more embodiments, the alcohol is a biologically activealcohol. In an embodiment, biologically active alcohol possesseskeratolytic activities. Examples of keratolytically active alcoholsuitable according to the present invention include ortho-, meta- andpara-hydroxyalkylbenzoate, salicylic acid, ortho-, meta-, andpara-dihydroxybenzene, ortho-, meta-, and para-hydroxytoluene,alpha-hydroxy acid, retinol, and derivatives thereof such as provided inU.S. Pat. No. 6,180,669, which is incorporated herein by reference. Inanother embodiment, the biologically active alcohol is selected from thegroup consisting of steroidal hormones, steroidal anti-inflammatoryagents, vitamin E and vitamin D, such as provided in U.S. Pat. Appl.20040191196, which is incorporated herein by reference.

In an embodiment of the present invention, the dicarboxylic acid isincorporated in the foamable composition in a safe and effective amount.The term “safe and effective” means an amount of an active agent thatexerts a therapeutic effect on a specific disorder, without causingadverse effects that may prohibit the use of said active agent in thetreatment of said disorder. The dicarboxylic acid can be incorporated inthe foamable composition of the present invention in a concentrationbetween about 0.1% and about 25%, more preferably between about 1% andabout 20%.

In an embodiment of the present invention, the dicarboxylic acid isazelaic acid, and its concentration in the composition is between 5% and25%, or between 10% and 20%.

In one or more embodiment, the dicarboxylic acid is present in thecomposition in an ionized state. The first and second pKa values for adicarboxylic acid are different from one another. Depending on the pH ofthe composition and the specific first and second pKa of thedicarboxylic acid, said dicarboxylic acid can be non-ionized (bothcarboxy groups are in their acid state); semi-ionized (one carboxy groupis in an acid state and the second is in an anionic state); ordoubly-ionized, wherein both carboxy groups are anionic. For example, inmaleic acid the first pKa is 1.9 and the second pKa is 4.4. Therefore,if the pH of the composition is between about 2 and about 4.3, themaleic acid is mostly semi-ionized and at pH above 4.5 the maleic acidis mostly doubly-ionized. Likewise, in the case of azelaic acid thefirst pKa is about 4.5 and the second pKa is about 5.3. Therefore, ifthe pH of the composition is below 4.5, the azelaic acid is non-ionized;between about 4.5 and about 5.3, it is mostly semi-ionized and at a pHabove 5.3, the azelaic acid is mostly doubly-ionized.

The ionization state of the dicarboxylic acid has influence on itstherapeutic potential. On one hand, if the dicarboxylic acid is doublyanionic, its penetration into the skin will be very low, due to thelipophilic nature of the skin. On the other hand, the non-ionic state isavailable at very low (acidic) pH values, which can cause skinirritation.

Hence, in one or more embodiments, the pH of the composition is adjustedto a value between the first and second pKa values of the dicarboxylicacid. For example, in the case of azelaic acid, the pH is adjusted inthe range from about 2.0 to about 4.5, preferably in the range fromabout 3.0 to about 4.5. Thus, in an embodiment of the present invention,the dicarboxylic acid is azelaic acid, and the pH of the composition isadjusted in the range from about 4.0 to about 6.0, preferably in therange from about 4.5.0 to about 5.3.

Dicarboxylic acid esters are considered excellent emollients and theirinclusion in a composition which is intended for topical applicationcontributes to the overall improvement of skin condition. Emollientdicarboxylic esters typically include an alkyl alcohol moiety, whereinsaid alkyl alcohol has a carbon chain of at least one or two or morecarbon atoms. In certain embodiments, the alkyl alcohol is a branchedalkyl, such as isopropyl alcohol; and in other embodiments the alkylalcohol has a long carbon backbone, e.g., a carbon chain length of 6-18.

Dicarboxylic acid esters can be complex substances. One example is TU2100 (Nonanedioic acid, bis[(2-(ethoxycarbonyl)phenyl] ester). It isalso known as Azelaoyl di(ethyl salicylate) and has a CAS RegistryNumber: [207972-39-2] and is a solid. TU-2100 is a “non-simple” diester;with a high molecular weight, and a melting point of 34-36, which isrelatively low with reference to its molecular weight.

Non-limiting examples of emollient dicarboxylic acid esters includediisobutyl adipate, diisopropyl adipate, diisopropyl sebacate,diisosteary dimer dilinoleate, diisostearyl fumerate, diisopropyldimerate, diethyl adipate, diethyl sebacate, diethylhexyl adipate,diethylhexyl malate, dioctyl malate, diethyl succinate, and dioctylsebacate. Other diccarboxylic acid esters are dimethyl phthalate,diethyl phthalate, diethyl sebacate, diisopropyl dimerate, dibutylsebacate, dibutyl phthalate and dioctyl phthalate. Additionallydicarboxylic acid esters are capable of solubilizing active componentswhich are difficult to dissolve by other oils. Furthermore, certaindicarboxylic acid esters, such as diisopropyl adipate and dimethylsebacate are known to enhance the skin penetration of active agents.Hence in an embodiment of the present invention, the dicarboxylic acidester is incorporated in the foamable composition in an amount, suitableto exert its emollient effect, solubilizing effect or skin penetrationenhancing effect. In one or more embodiments, the dicarboxylic acidester is incorporated in the foamable composition of the presentinvention in a concentration between about 0.1% and about 30%, morepreferably between about 1% and about 25%.

In one embodiment, the dicarboxylic acid ester is diisopropyl adipate(DISPA), in an amount between about 0.1% and about 30%, or about 1% andabout 25%.

As can be appreciated by the discussion above, there is a varied rangeof dicarboxylic acids and esters; some are solid, some are liquid, someare water soluble, some are slightly soluble and others are insoluble inwater. There is also a varied range of functions and physicalproperties. Some are active agents and others are solvents and some arepenetration enhancers. The challenges of making a uniform solution ofsolid DCA's without crystal formation or precipitation or a uniformsuspension of insoluble agent, or using a DCA to solubilise a substancewhich is otherwise insoluble or as an emollient or as a penetrationenhancer or more than one of them are as varied as their differentnatures and properties as may be appreciated by a man of the art. Inother words each agent has its own properties and challenges which areinterrelated to the objectives and other ingredients of the formulation

The sensory properties of foams containing a dicarboxylic acid or adicarboxylic acid ester are favorable, as revealed by consumer paneltests.

Foam Adjuvant

Optionally, the foamable vehicle further includes a foam adjuvantselected from the group consisting of a fatty alcohol having 15 or morecarbons in their carbon chain; a fatty acid having 16 or more carbons intheir carbon chain; fatty alcohols, derived from beeswax and including amixture of alcohols, a majority of which has at least 20 carbon atoms intheir carbon chain; a fatty alcohol having at least one double bond; afatty acid having at least one double bond; a branched fatty alcohol; abranched fatty acid and a fatty acid substituted with a hydroxyl group.

Additional Organic Carrier

Optionally, the foamable vehicle further includes at least oneadditional organic carrier selected from the group consisting of ahydrophobic organic carrier, an emollient and mixtures thereof, at aconcentration of about 2% to about 50% by weight. The hydrophobicsolvent and/or the emollient can be selected from the group consistingof mineral oil, triglycerides, capric/caprylic triglyceride, alkylesters of fatty acids such as isopropyl palmitate, isopropylisostearate, octyl palmitate, cetyl lactate, cetyl ricinoleate,tocopheryl acetate, acetylated lanolin alcohol, cetyl acetate, phenyltrimethicone, glyceryl oleate, tocopheryl linoleate, wheat germglycerides, arachidyl propionate, myristyl lactate, decyl oleate,ricinoleate, isopropyl lanolate, pentaerythrityl tetrastearate,neopentylglycol dicaprylate/dicaprate, isononyl isononanoate,isotridecyl isononanoate, myristyl myristate, triisocetyl citrate, octyldodecanol, maleated soybean oil, unsaturated or polyunsaturated oils,such as olive oil, corn oil, soybean oil, canola oil, cottonseed oil,coconut oil, sesame oil, sunflower oil, borage seed oil, syzigiumaromaticum oil, hempseed oil, herring oil, cod-liver oil, salmon oil,flaxseed oil, wheat germ oil, evening primrose oils; essential oils; andsilicone oils, such as dimethicone, cyclomethicone, polyalkyl siloxane,polyaryl siloxane, polyalkylaryl siloxane, a polyether siloxanecopolymer and a poly(dimethylsiloxane)-(diphenyl-siloxane) copolymer.

In an embodiment of the present invention, the organic carrier is apolypropylene glycol alkyl ether (PPG alkyl ether). PPG alkyl ethers areliquid, water-insoluble propoxylated fatty alcohols, having themolecular formula of RO(CH₂CHOCH₃)_(n); wherein “R” is astraight-chained or branched C₄ to C₂₂ alkyl group; and “n” is in therange between 4 and about 50. They are organic liquids that function asskin-conditioning agent in pharmaceutical and cosmetic formulations.Non-limiting exemplary PPG alkyl ethers include PPG stearyl ethers andPPG Butyl Ether. Preferred PPG alky ethers according to the presentinvention include PPG-15 Stearyl Ether, PPG-2 Butyl Ether, PPG-9-13Butyl Ether and PPG-40 Butyl Ether.

According to a preferred embodiment, the organic carrier does notcontain petrolatum, which is also termed “white petrolatum” and“Vaseline”. Petrolatum often forms an impermeable occlusive barrier, sothat metabolic products and excreta from damaged tissue are not easilyremoved or drained away. Furthermore, it is difficult for the activedrug dissolved in the carrier to pass through the white petrolatumbarrier layer into the treated tissue, so the efficacy of the drug isreduced. An additional disadvantage of petroleum jelly-based productsrelates to the greasy feeling left following their topical applicationonto the skin, mucosal membranes and wounds causing inconvenience to theuser, thereby decreasing treatment compliance.

Polymeric Agent

The composition of the present invention contains a polymeric agentselected from the group consisting of a bioadhesive agent, a gellingagent, a film forming agent and a phase change agent. A polymeric agentenhances the creation of foam having fine bubble structure, which doesnot readily collapse upon release from the pressurized aerosol can. Thepolymeric agent serves to stabilize the foam composition and to controldrug residence in the target organ.

Exemplary polymeric agents include, in a non-limiting manner,naturally-occurring polymeric materials, such as locust bean gum, sodiumalginate, sodium caseinate, egg albumin, gelatin agar, carrageenin gum,sodium alginate, xanthan gum, quince seed extract, tragacanth gum, guargum, cationic guars, hydroxypropyl guar gum, starch, amine-bearingpolymers such as chitosan; acidic polymers obtainable from naturalsources, such as alginic acid and hyaluronic acid; chemically modifiedstarches and the like, carboxyvinyl polymers, polyvinylpyrrolidone,polyvinyl alcohol, polyacrylic acid polymers, polymethacrylic acidpolymers, polyvinyl acetate polymers, polyvinyl chloride polymers,polyvinylidene chloride polymers and the like.

Additional exemplary polymeric agents include semi-synthetic polymericmaterials such as cellulose ethers, such as methylcellulose,hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxy propylmethyl cellulose, methylhydroxyethylcellulose,methylhydroxypropylcellulose, hydroxyethylcarboxymethylcellulose,carboxymethyl cellulose, carboxymethylcellulosecarboxymethylhydroxyethylcellulose, and cationic celluloses, carbomer(homopolymer of acrylic acid is crosslinked with an allyl etherpentaerythritol, an allyl ether of sucrose, or an allyl ether ofpropylene, such as Carbopol® 934, Carbopol® 940, Carbopo® 941, Carbopol®980 and Carbopol® 981, pemulen and aluminum starch octenylsuccinate(ASOS). Polyethylene glycol, having molecular weight of 1000 or more(e.g., PEG 1,000, PEG 4,000, PEG 6,000 and PEG 10,000) also have gellingcapacity and while they are considered herein as “secondary polarsolvents”, as detailed herein, they are also considered polymericagents.

In one or more embodiments the polymeric agents have emulsifyingproperties. In certain preferred embodiments the polymeric agent is aderivatized hydrophilic polymer with hydrophobic alkyl moieties Othertypes that may also a similar stabilizing effect are silicone copolymersand derivatized starch ASOS.

Mixtures of the above polymeric agents are contemplated.

The concentration of the polymeric agent should be selected so that thecomposition, after filling into aerosol canisters, is flowable, and canbe shaken in the canister. In one or more embodiments, the concentrationof the polymeric agent is selected such that the viscosity of thecomposition, prior to filling of the composition into aerosol canisters,is less than 12,000 CPs, and more preferably, less than 10,000 CPs.

Surface Active Agent

The composition of the present invention further contains asurface-active agent. Surface-active agents (also termed “surfactants”)include any agent linking oil and water in the composition, in the formof emulsion. A surfactant's hydrophilic/lipophilic balance (HLB)describes the emulsifier's affinity toward water or oil. HLB is definedfor non-ionic surfactants. The HLB scale ranges from 1 (totallylipophilic) to 20 (totally hydrophilic), with 10 representing an equalbalance of both characteristics. Lipophilic emulsifiers formwater-in-oil (w/o) emulsions; hydrophilic surfactants form oil-in-water(o/w) emulsions. The HLB of a blend of two emulsifiers equals the weightfraction of emulsifier A times its HLB value plus the weight fraction ofemulsifier B times its HLB value (weighted average). In many cases asingle surfactant may suffice. In other cases a combination of two ormore surfactants is desired. Reference to a surfactant in thespecification can also apply to a combination of surfactants or asurfactant system. As will be appreciated by a person skilled in the artwhich surfactant or surfactant system is more appropriate is related tothe vehicle and intended purpose. In general terms a combination ofsurfactants is usually preferable where the vehicle is an emulsion. Inan emulsion environment a combination of surfactants can be significantin producing breakable forms of good quality. It has been furtherdiscovered that the generally thought considerations for HLB values forselecting a surfactant or sufactant combination are not always bindingfor emulsions and that good quality foams can be produced with asurfactant or surfactant combination both where the HLB values are in ortowards the lipophilic side of the scale and where the HLB values are inor towards the hydrophilic side of the scale. Surfactants also play arole in foam formation where the foamable formulation is a single phasecomposition.

According to one or more embodiments the composition contains a singlesurface active agent having an HLB value between about 2 and 9, or morethan one surface active agent and the weighted average of their HLBvalues is between about 2 and about 9. Lower HLB values may in certainembodiments be more applicable to water in oil emulsions.

According to one or more embodiments the composition contains a singlesurface active agent having an HLB value between about 7 and 14, or morethan one surface active agent and the weighted average of their HLBvalues is between about 7 and about 14. Mid range HLB values may incertain embodiments be more suitable for oil in water emulsions.

According to one or more other embodiments the composition contains asingle surface active agent having an HLB value between about 9 andabout 19, or more than one surface active agent and the weighted averageof their HLB values is between about 9 and about 19. In a waterless orsubstantially waterless environment a wide range of HLB values may besuitable.

Preferably, the composition of the present invention contains anon-ionic surfactant. Nonlimiting examples of possible non-ionicsurfactants include a polysorbate, polyoxyethylene (20) sorbitanmonostearate, polyoxyethylene (20) sorbitan monooleate, apolyoxyethylene fatty acid ester, Myrj 45, Myrj 49, Myrj 52 and Myrj 59;a polyoxyethylene alkyl ether, polyoxyethylene cetyl ether,polyoxyethylene palmityl ether, polyethylene oxide hexadecyl ether,polyethylene glycol cetyl ether, steareths such as steareth 2, brij 21,brij 721, brij 38, brij 52, brij 56 and brij W1, a sucrose ester, apartial ester of sorbitol and its anhydrides, sorbitan monolaurate,sorbitan monolaurate, a monoglyceride, a diglyceride, isoceteth-20 andmono-, di- and tri-esters of sucrose with fatty acids. In certainembodiments, suitable sucrose esters include those having high monoestercontent, which have higher HLB values.

In certain embodiments with DCA esters as emollient, surfactants areselected which can provide a close packed sufacant layer separating theoil and water phases. To achieve such objectives combinations of atleast two surfactants are selected. Preferrably, they should be complexemulgators and more preferably they should both be of a similarmolecular type. For example, a pair of ethers like steareth 2 andsteareth 21, or a pair of esters for example, PEG-40 stearate andpolysorbate 80. In Certain circumstances POE esters cannot be used and acombination of sorbitan laurate and sorbitan stearate or a combinationof sucrose stearic acid ester mixtures and sodium laurate may be used.All these combinations due to heir versatility and strength may also beused satisfactorily and effectively with solutions of DCA's and withsolid/crystalline suspensions, although the amounts and proportion maybe varied according to the formulation and its objectives as will beappreciated by a man of the art.

It has been discovered also that by using a derivatized hydrophilicpolymer with hydrophobic alkyl moieties as a polymeric emulsifier suchas pemulen it is possible to stabilize the emulsion better about or atthe region of phase reversal tension. Other types of derivatizedpolymers like silicone copolymers, derivatized starch [Aluminum StarchOctenylsuccinate (ASOS)]/[DRY-FLO AF Starch], and derivatized dexrin mayalso a similar stabilizing effect.

A series of dextrin derivative surfactants prepared by the reaction ofthe propylene glycol polyglucosides with a hydrophobicoxirane-containing material of the glycidyl ether are highlybiodegradable. [Hong-Rong Wang and Keng-Ming Chen, Colloids and SurfacesA: Physicochemical and Engineering Aspects Volume 281, Issues 1-3, 15Jun. 2006, Pages 190-193].

Non-limiting examples of non-ionic surfactants that have HLB of about 7to about 12 include steareth 2 (HLB˜4.9); glyceryl monostearate/PEG 100stearate (Av HLB˜11.2); stearate Laureth 4 (HLB˜9.7) and cetomacrogolether (e.g., polyethylene glycol 1000 monocetyl ether).

Non-limiting examples of preferred surfactants, which have a HLB of 4-19are set out in the Table below:

Surfactant HLB steareth 2 ~4.9 glyceryl monostearate/PEG 100 stearate Av~11.2 Glyceryl Stearate ~4 Steareth-21 ~15.5 peg 40 stearate ~16.9polysorbate 80 ~15 sorbitan stearate ~4.7 laureth 4 ~9.7 Sorbitanmonooleate (span 80) ~4.3 ceteareth 20 ~15.7 steareth 20 ~15.3 ceteth 20~15.7 Macrogol Cetostearyl Ether ~15.7 ceteth 2 (Lipocol C-2) ~5.3PEG-30 Dipolyhydroxystearate ~5.5 sucrose distearate (Sisterna SP30) ~6polyoxyethylene (100) stearate ~18.8

More exemplary stabilizing surfactants which may be suitable for use inthe present invention are found below.

PEG-Fatty Acid Monoester Surfactants

Chemical name Product example name HLB PEG-30 stearate Myrj 51 >10PEG-40 laurate Crodet L40 (Croda) 17.9 PEG-40 oleate Crodet O40 (Croda)17.4 PEG-45 stearate Nikkol MYS-45 (Nikko) 18 PEG-50 stearate Myrj53 >10 PEG-100 stearate Myrj 59, Arlacel 165 (ICI) 19PEG-Fatty Acid Diester Surfactants:

Chemical name Product example name HLB PEG-4 dilaurate Mapeg .RTM. 200DL (PPG), 7 Kessco .RTM.PEG 200 DL (Stepan), LIPOPEG 2-DL (Lipo Chem.)PEG-4 distearate Kessco .RTM. 200 5 DS (Stepan.sub) PEG-32 dioleateKessco .RTM. PEG 1540 DO 15 (Stepan) PEG-400 dioleate Cithrol 4DO series(Croda) >10 PEG-400 disterate Cithrol 4DS series (Croda) >10 PEG-20glyceryl oleate Tagat .RTM. O (Goldschmidt) >10Transesterification Products of Oils and Alcohols

Chemical name Product example name HLB PEG-30 castor oil Emalex C-30(Nihon Emulsion) 11 PEG-40 hydrogenated Cremophor RH 40 (BASF), 13castor oil Croduret (Croda), Emulgin HRE 40 (Henkel)Polyglycerized Fatty Acids, Such as:

Chemical name Product example name LB Polyglyceryl-6 dioleate Caprol.RTM. 6G20 (ABITEC); 8.5 PGO-62 (Calgene), PLUROL OLEIQUE CC 497(Gattefosse)HodagPEG-Sorbitan Fatty Acid Esters

Chemical name Product example name HLB PEG-20 sorbitan Tween-20(Atlas/ICI), Crillet 1 17 monolaurate (Croda), DACOL MLS 20 (Condea)PEG-20 sorbitan Tween 40 (Atlas/ICI), Crillet 2 16 Monopalmitate (Croda)PEG-20 sorbitan Tween-60 (Atlas/ICI), Crillet 3 15 monostearate (Croda)PEG-20 sorbitan Tween-80 (Atlas/ICI), Crillet 4 15 monooleate (Croda)Polyethylene Glycol Alkyl Ethers

Chemical name Product example name HLB PEG-2 oleyl ether oleth-2 Brij92/93 (Atlas/ICI) 4.9 PEG-3 oleyl ether oleth-3 Volpo 3 (Croda) <10PEG-5 oleyl ether oleth-5 Volpo 5 (Croda) <10 PEG-10 oleyl etheroleth-10 Volpo 10 (Croda), 12 Brij 96/97 (Atlas/ICI) PEG-20 oleyl etheroleth-20 Volpo 20 (Croda), 15 Brij 98/99 (Atlas/ICI) PEG-4 lauryl etherlaureth-4Brij 30 (Atlas/ICI) 9.7 PEG-23 lauryl ether laureth-23Brij 35(Atlas/ICI) 17 PEG-10 stearyl ether Brij 76 (ICI) 12 PEG-2 cetyl etherBrij 52 (ICI) 5.3Sugar Ester Surfactants

Chemical name Product example name HLB Sucrose distearate Sisterna SP50,Surfope 1811 11Sorbitan Fatty Acid Ester Surfactants

Chemical name Product example name HLB Sorbitan monolaurate Span-20(Atlas/ICI), Crill 1 8.6 (Croda), Arlacel 20 (ICI) Sorbitanmonopalmitate Span-40 (Atlas/ICI), Crill 2 6.7 (Croda), Nikkol SP-10(Nikko) Sorbitan monooleate Span-80 (Atlas/ICI), Crill 4 4.3 (Croda),Crill 50 (Croda) Sorbitan monostearate Span-60 (Atlas/ICI), Crill 3 4.7(Croda), Nikkol SS-10 (Nikko)

In one or more embodiments the surface active agent is a complexemulgator in which the combination of two or more surface active agentscan be more effective than a single surfactant and provides a morestable emulsion or improved foam quality than a single surfactant. Forexample and by way of non-limiting explanation it has been found that bychoosing say two surfactants, one hydrophobic and the other hydrophilicthe combination can produce a more stable emulsion than a singlesurfactant. Preferably, the complex emulgator comprises a combination ofsurfactants wherein there is a difference of about 4 or more unitsbetween the HLB values of the two surfactants or there is a significantdifference in the chemical nature or structure of the two or moresurfactants.

Specific non limiting examples of surfactant systems are, combinationsof polyoxyethylene alkyl ethers, such as Brij 59/Brij 10; Brij 52/Brij10; Steareth 2/Steareth 20; Steareth 2/Steareth 21 (Brij 72/Brij 721);combinations of polyoxyethylene stearates such as Myrj 52/Myrj 59;combinations of sucrose esters, such as Surphope 1816/Surphope 1807;combinations of sorbitan esters, such as Span 20/Span 80; Span 20/Span60; combinations of sucrose esters and sorbitan esters, such as Surphope1811 and Span 60; combinations of liquid polysorbate detergents and PEGcompounds, such as Tween 80/PEG-40 stearate; methyl glucasosequistearate; polymeric emulsifiers, such as Permulen (TRI or TR2);liquid crystal systems, such as Arlatone (2121), Stepan (Mild RM1),Nikomulese (41) and Montanov (68) and the like.

In certain embodiments the surfactant is preferably one or more of thefollowing: a combination of steareth-2 and steareth-21 on their own orin combination with glyceryl monostearate (GMS); in certain otherembodiments the surfactant is a combination of polysorbate 80 and PEG-40stearate. In certain other embodiments the surfactant is a combinationof glyceryl monostearate/PEG 100 stearate. In certain other embodimentsthe surfactant is a combination of two or more of stearate 21, PEG 40stearate, and polysorbate 80. In certain other embodiments thesurfactant is a combination of two or more of laureth 4, span80, andpolysorbate 80. In certain other embodiments the surfactant is acombination of two or more of GMS and ceteareth. In certain otherembodiments the surfactant is a combination of two or more of steareth21, ceteareth 20, ceteth 2 and laureth 4 In certain other embodimentsthe surfactant is a combination of ceteareth 20 and polysorbate 40stearate. In certain other embodiments the surfactant is a combinationof span 60 and GMS.

In certain other embodiments the surfactant is one or more of sucrosestearic acid esters, sorbitan laureth, and sorbitan stearate.

In one or more embodiments the stability of the composition can beimproved when a combination of at least one non-ionic surfactant havingHLB of less than 9 and at least one non-ionic surfactant having HLB ofequal or more than 9 is employed. The ratio between the at least onenon-ionic surfactant having HLB of less than 9 and the at least onenon-ionic surfactant having HLB of equal or more than 9, is between 1:8and 8:1, or at a ratio of 4:1 to 1:4. The resultant HLB of such a blendof at least two emulsifiers is preferably between about 9 and about 14.

Thus, in an exemplary embodiment, a combination of at least onenon-ionic surfactant having HLB of less than 9 and at least onenon-ionic surfactant having HLB of equal or more than 9 is employed, ata ratio of between 1:8 and 8:1, or at a ratio of 4:1 to 1:4, wherein theHLB of the combination of emulsifiers is preferably between about 5 andabout 18.

In certain cases, the surface active agent is selected from the group ofcationic, zwitterionic, amphoteric and ampholytic surfactants, such assodium methyl cocoyl taurate, sodium methyl oleoyl taurate, sodiumlauryl sulfate, triethanolamine lauryl sulfate and betaines.

Many amphiphilic molecules can show lyotropic liquid-crystalline phasesequences depending on the volume balances between the hydrophilic partand hydrophobic part. These structures are formed through themicro-phase segregation of two Many amphiphilic molecules can showlyotropic liquid-crystalline phase sequences depending on the volumebalances between the hydrophilic part and hydrophobic part. Thesestructures are formed through the micro-phase segregation of twoincompatible components on a nanometer scale. Soap is an everydayexample of a lyotropic liquid crystal. Certain types of surfactants tendto form lyotropic liquid crystals in emulsions interface (oil-in-water)and exert a stabilizing effect

In one or more embodiments the surfactant is a surfactant or surfactantcombination is capable of or which tends to form liquid crystals.Surfactants which tend to form liquid crystals may improve the qualityof foams. Non limiting examples of surfactants with postulated tendencyto form interfacial liquid crystals are: phospholipids, alkylglucosides, sucrose esters, sorbitan esters.

In one or more embodiments the at least one surface active agent isliquid.

In one or more embodiments the at least one surface active agent issolid, semi solid or waxy.

It should be noted that HLB values may not be so applicable to non ionicsurfactants, for example, with liquid crystals or with silicones. AlsoHLB values may be of lesser significance in a waterless or substantiallynon-aqueous environment.

In one or more embodiments the surfactant can be, a surfactant systemcomprising of a surfactant and a co surfactant, a waxy emulsifier, aliquid crystal emulsifier, an emulsifier which is solid or semi solid atroom temperature and pressure, or combinations of two or more agents inan appropriate proportion as will be appreciated a person skilled in theart. Where a solid or semi solid emulsifier combination is used it canalso comprise a solid or semi solid emulsifier and a liquid emulsifier.

In one or more embodiments of the present invention, the surface-activeagent includes at least one non-ionic surfactant. Ionic surfactants areknown to be irritants. Therefore, non-ionic surfactants are preferred inapplications including sensitive tissue such as found in most mucosaltissues, especially when they are infected or inflamed. Non-ionicsurfactants alone can provide formulations and foams of good orexcellent quality in the carriers and compositions of the presentinvention.

Thus, in a preferred embodiment, the surface active agent, thecomposition contains a non-ionic surfactant. In another preferredembodiment the composition includes a mixture of non-ionic surfactantsas the sole surface active agent. Yet, in additional embodiments, thefoamable composition includes a mixture of at least one non-ionicsurfactant and at least one ionic surfactant in a ratio in the range ofabout 100:1 to 6:1. In one or more embodiments, the non-ionic to ionicsurfactant ratio is greater than about 6:1, or greater than about 8:1;or greater than about 14:1, or greater than about 16:1, or greater thanabout 20:1. In further embodiments, surface active agent comprises acombination of a non-ionic surfactant and an ionic surfactant, at aratio of between 1:1 and 20:1

In one or more embodiments of the present invention, a combination of anon-ionic surfactant and an ionic surfactant (such as sodium laurylsulphate and cocamidopropylbetaine) is employed, at a ratio of between1:1 and 20:1, or at a ratio of 4:1 to 10:1; for example, about 1:1,about 4:1, about 8:1, about 12:1, about 16:1 and about 20:1 or at aratio of 4:1 to 10:1, for example, about 4:1, about 6:1, about 8:1 andabout 10:1.

In selecting a suitable surfactant or combination thereof it should beborne in mind that the upper amount of surfactant that may be used maybe limited by the shakability of the composition. If the surfactant isnon liquid, it can make the formulation to viscous or solid. This can beparticularly significant if the formulation has high molecular weight,e.g., a high molecular weight PEG or polymeric agents or petroleum or ifthe surfactants are large. Solvents and polymeric agents which have highmolecular weight and are very viscous or solid or waxy (e.g., Peg 1500,2000, etc. or petrolatum) can exacerbate the effect of a waxy or solidsurfactant on shakability or flowability In general terms, as the amountof non-liquid surfactant is increased the shakability of the formulationreduces until a limitation point is reached where the formulationbecomes non shakable and unsuitable. Thus in one embodiment, aneffective amount of surfactant may be used provided the formulationremains shakable. In other certain exceptional embodiments the upperlimit may be determined by flowability such as in circumstances wherethe composition is marginally or apparently non-shakable. Theformulation is sufficiently flowable to be able to flow through anactuator valve and be released and still expand to form a good qualityfoam.

In certain embodiments of the present invention the amount of surfactantor combination of surfactants is between about 0.05% to about 20%;between about 0.05% to about 15%. or between about 0.05% to about 10%.In a preferred embodiment the concentration of surface active agent isbetween about 0.2% and about 8%. In a more preferred embodiment theconcentration of surface active agent is between about 1% and about 6%.

In some embodiments, it is desirable that the surface active agent doesnot contain a polyoxyethylene (POE) moiety, such as polysorbatesurfactants, POE fatty acid esters, and POE alkyl ethers, because theactive agent is incompatible with such surface active agents. Forexample, the active agent pimecrolimus is not stable the presence of POEmoieties, yet benefits greatly from the use of dicarboxylic esters aspenetration enhancers. In such cases, alternative surface active agentsare employed. In an exemplary manner, POE-free surfactants includenon-ethoxylated sorbitan esters, such as sorbitan monopalmitate,sorbitan monostearate, sorbitan tristearate, sorbitan monooleate,sorbitan trioleate, sorbitan monolaurate and sorbitan sesquioleate;glycerol fatty acid esters, such as glycerol monostearate and glycerolmonooleate; mono-, di- and tri-esters of sucrose with fatty acids(sucrose esters), sucrose stearate, sucrose distearate sucrose palmitateand sucrose laurate; and alkyl polyglycosides, such as lauryldiglucoside.

If the composition as formulated is a substantially non shakablecomposition it is nevertheless possible as an exception in the scope ofthe present invention for the formulation to be flowable to a sufficientdegree to be able to flow through an actuator valve and be released andstill expand to form a good quality foam. This surprising and unusualexception may be due one or more of a number of factors such as the highviscosity, the softness, the lack of crystals, the pseudoplastic or semipseudo plastic nature of the composition and the dissolution of thepropellant into the composition.

In one or more embodiments of the present invention, the surface-activeagent includes mono-, di- and tri-esters of sucrose with fatty acids(sucrose esters), prepared from sucrose and esters of fatty acids or byextraction from sucro-glycerides. Suitable sucrose esters include thosehaving high monoester content, which have higher

Phase Inversion and Tension

Phase inversion is a factor in the preparation and stabilization ofemulsions and can be both an aid and a detriment. Phase inversioninvolves the change of emulsion type from o/w to w/o or vice versa.Prior to phase inversion occurring there is a tension in the emulsionwhich if destabilized or driven will lead to phase inversion and ifcontrolled or ameliorated or dissipated will result in a more stableemulsion. The occurrence of phase inversion during preparation can be asign of instability. If controlled, it can result in a finer product butif due to other factors after the the emulsion was prepared it can causeproblems. Inversion can occur by for example adding calcium chloride toan o/w emulsion stabilized with sodium stearate to form calciumstearate. Inversion can also occur as the product of changes to thephase-volume ratio. For example if a small amount of water is added tosurfactant mixed with oil and agitated aw/o emulsion is formed As theamount of water added is gradually increased a point will be reachedwhere the water and emulsifier envlop the oil as small droplets to forman o/w emulsion. The amount of each ingredient including the surfactantswill have their part to play in the phenomenum.

Substantially Alcohol-Free

According to one or more embodiments, the foamable composition issubstantially alcohol-free, i.e., free of short chain alcohols. Shortchain alcohols, having up to 5 carbon atoms in their carbon chainskeleton and one hydroxyl group, such as ethanol, propanol, isopropanol,butaneol, iso-butaneol, t-butaneol and pentanol, are considered lessdesirable solvents or polar solvents due to their skin-irritatingeffect. Thus, the composition is substantially alcohol-free and includesless than about 5% final concentration of lower alcohols, preferablyless than about 2%, more preferably less than about 1%.

Substantially Non Aqueous

In certain cases, the active agent degrades in the presence of water,and therefore, in such cases the present of water in the composition isnot desirable. Thus, in certain preferred embodiments, the compositionis substantially non-aqueous. The term “substantially non-aqueous” or“substantially waterless” is intended to indicate that the compositionhas a water content below about 5%, preferably below about 2%, such asbelow about 1.5%. In certain other preferred embodiments the compositionis non aqueous or waterless.

By non aqueous or waterless is meant that the composition contains no orsubstantially no, free or unassociated or absorbed water. It will beunderstood by a person of the art that the waterless solvents andsubstances miscible with them of the present invention can behydrophilic and can contain water in an associated or unfree or absorbedform and may absorb water from the atmosphere and the ability to do sois its hygroscopic water capacity. It is intended that essentiallynon-aqueous formulations are included within its scope such that theformulations may have present a small amount of water. In someembodiments the composition ingredients are pretreated to reduce, removeor eliminate any residual or associated or absorbed water.

Shakability

‘Shakability’ means that the composition contains some or sufficientflow to allow the composition to be mixed or remixed on shaking. Thatis, it has fluid or semi fluid properties. In some very limited casespossibly aided by the presence of silicone it may exceptionally bepossible to have a foamable composition which is flowable but notapparently shakable.

Breakability

A breakable foam is one that is thermally stable, yet breaks under sheerforce.

The breakable foam of the present invention is not “quick breaking”,i.e., it does not readily collapse upon exposure to body temperatureenvironment. Sheer-force breakability of the foam is clearlyadvantageous over thermally induced breakability, since it allowscomfortable application and well directed administration to the targetarea.

Modulating Agent

The term modulating agent is used to describe an agent which can improvethe stability of or stabilize a foamable carrier or composition and oran active agent by modulating the effect of a substance or residuepresent in the carrier or composition.

In one or more embodiments the modulating agent is used in a water inoil or oil in water emulsion. In one or more other embodiments themodulating agent is used in a unique waterless emulsion.

In certain embodiments the substance or residue may for example beacidic or basic and potentially alter pH in an emulsion environment orit may be one or more metal ions which may act as a potential catalystin an emulsion environment.

In certain other embodiments the substance or residue may for example beacidic or basic and potentially alter an artificial pH in a waterless orsubstantially non aqueous environment or it may be one or more metalions which may act as a potential catalyst in a waterless orsubstantially non aqueous environment.

In one or more embodiments the modulating agent is used to describe anagent which can affect pH in an aqueous solution. The agent can be anyof the known buffering systems used in pharmaceutical or cosmeticformulations as would be appreciated by a man of the art. It can also bean organic acid, a carboxylic acid, a fatty acid an amino acid, anaromatic acid, an alpha or beta hydroxyl acid an organic base or anitrogen containing compound.

In one or more further embodiments the modulating agent is used todescribe an agent, which is a chelating or sequestering or complexingagent that is sufficiently soluble or functional in the solvent toenable it to “mop up” or “lock” metal ions.

In an embodiment modulating agent is used to describe an agent which caneffect pH in an aqueous solution the term modulating agent moreparticularly means an acid or base or buffer system or combinationsthereof, which is introduced into or is present in and acts to modulatethe ionic or polar characteristics and any acidity or basesity balanceof an emulsion carrier, composition, foamable carrier or foamablecomposition or resultant foam of the present invention.

In other embodiments modulating agent is used to describe an agent whichcan effect pH in an aqueous solution the term modulating agent moreparticularly means an acid or base or buffer system or combinationsthereof, which is introduced into or is present in and acts to modulatethe ionic or polar characteristics and any acidity or basesity balanceof a waterless or substantially non aqueous carrier, composition,foamable carrier or foamable composition or resultant foam of thepresent invention.

The substance or residue can be introduced into the formulation from anyone or more of the ingredients, some of which themselves may have acidicor basic properties. For example the polymer or solvent may containbasic residues in which case it may be desirable or beneficial to add anacid. Alternatively the surfactant may contain some acid residues inwhich case the addition of a base may be desirable and beneficial. Insome cases more than one ingredient may contain residues which mayameliorate or compound their significance. For example if one ingredientprovided weak acid residues and another stronger acid residues the pH inan emulsion environment (or artificial pH in a waterless environment)should be lower. In contrast if one residue was acid and the other basicthe net effect in the formulation maybe significantly reduced. In somecircumstances the active ingredient may favor an acidic pH or moresignificantly may need to be maintained at a certain acidic pH otherwiseit may readily isomerize, chemically react or breakdown, in which caseintroducing acidic components such as an acidic polymer might be ofhelp. In an embodiment of the present invention sufficient modulatingagent is added to achieve a pH in which the active agent is preferablystable. In another embodiment of the present invention sufficientmodulating agent is added to achieve an artificial pH in which theactive agent is preferably stable.

The terms pH, pKa, and pKb, buffers and the like are used in classicalmeasurements of an aqueous solution. Such measurements are artificial ina waterless environment. Nevertheless, reference to and descriptionbelow of such terms are made for convenience and clarity, since suchterms are well defined and understood with reference to aqueoussolutions and further due to the lack of an appropriate uniform way ofdescribing and identifying the artificial or virtual pH, pK etc in awaterless environment in relation to the present invention. Althoughpredictions of artificial pH can be made using dilution techniques ofmeasurements of waterless formulations diluted in water they areformulation sensitive and specific and have to be carefully calibratedwith complex formulas.

Waterless medium can be polar and protic yet it does not conform toclassical ionic behavior.

A buffer, as defined by Van Slyke [Van Slyke, J. Biol. Chem. 52, 525(1922)], is “a substance which by its presence in solution increases theamount of acid or alkali that must be added to cause unit change in pH.”

A buffer solution is a solution of a definite pH made up in such a waythat this pH alters only gradually with the addition of alkali or acid.Such a solution consists of a solution of a salt of the week acid in thepresence of the three acid itself. The pH of the solution is determinedby the dissociation equilibrium of the free acid.

An acid can be a strong acid or a weak acid. A strong acid is an acid,which is a virtually 100% ionized in solution. In contrast, a week acidis one which does not ionize fully. When it is dissolved in water. Thelower the value for pKa, the stronger is the acid and likewise, thehigher the value for pKa the weaker is the acid.

A base can be a strong base or a weak base. A strong base is something,which is fully ionic with 100% hydroxide ions. In contrast, a weak baseis one which does not convert fully into hydroxide ions in solution. Thelower the value for pKb, the stronger is the base and likewise, thehigher the value for pKb the weaker is the base.

In one or more embodiments of the present invention the modulating agentcomprises an organic compound.

In one or more preferred embodiments of the present invention thechelating agent is selected from the group consisting ofethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaaceticacid (DTPA), hydroxyethylenediaminetriacetic acid (HEDTA),nitrilotriacetic acid (NTA),O,O′-bis(2-aminoethyl)ethyleneglycol-N,N,N′,N′-tetraacetic acid (EGTA),trans-1,2-diaminocyclohexane-N,N,N′,N′-tetraacetic acid (CyDTA) or apharmaceutically acceptable salt thereof (normally as a sodium salt),more preferably EDTA, HEDTA and their salts; most preferably EDTA andits salts.

In one or more embodiments of the present invention a preferred nonlimiting example of the chelating agent is EDTA. Typically, thechelating and sequestering agent is present in the composition at alevel of up to about 5.0%, preferably 1.0 percent, by weight, of thecomposition.

In one or more embodiments of the present invention the modulating agentmay also be a preservative or an antioxidant or an ionization agent. Anypreservative, antioxidant or ionization agents suitable forpharmaceutical or cosmetic application may be used. Non limitingexamples of antioxidants are tocopherol succinate, propyl galate,butylated hydroxy toluene and butyl hydroxy anisol. Ionization agentsmay be positive or may be negative depending on the environment and theactive agent or composition that is to be protected. Ionization agentsmay for example act to protect or reduce sensitivity of active agents.Non limiting examples of positive ionization agents are benzyl coniumchloride, and cetyl pyridium chloride. Non limiting examples of negativeionization agents are sodium lauryl sulphate, sodium lauryl lactylateand phospholipids.

Humectant

A humectant is a substance that helps retain moisture and also preventsrapid evaporation. Non limiting examples are propylene glycol, propyleneglycol derivatives, glycerin, hydrogenated starch hydrosylate,hydrogenated lanolin, lanolin wax, D manitol, sorbitol, sodium2-pyrrolidone-5-carboxylate, sodium lactate, sodium PCA, solublecollagen, dibutyl phthalate, and gelatin. Other examples may be found inthe Handbook of Pharmaceutical Additives published by Gower.

Moisturizers

A moisturizer, is a substance that helps retain moisture or add backmoisture to the skin. Examples are allantoin, petrolatum, urea, lacticacid, sodium PCV, glycerin, shea butter, caprylic/capric/stearictriglyceride, candelilla wax, propylene glycol, lanolin, hydrogenatedoils, squalene, sodium hyaluronate and lysine PCA. Other examples may befound in the Handbook of Pharmaceutical Additives published by Gower.

Pharmaceutical compositions of the present invention may in one or moreembodiments usefully comprise in addition a heumectant or a moisturizeror combinations thereof.

Polar Solvent

Optionally, the foamable vehicle further includes at least one polarsolvent.

A “polar solvent” is an organic solvent, typically soluble in both waterand oil. Certain polar solvents, for example propylene glycol andglycerin, possess the beneficial property of a heumectant.

In one or more embodiments, the polar solvent is a heumectant.

In one or more embodiments, the polar solvent is a polyol. Polyols areorganic substances that contain at least two hydroxy groups in theirmolecular structure.

In one or more embodiments, the polar solvent contains an diol (acompound that contains two hydroxy groups in its molecular structure),such as propylene glycol (e.g., 1,2-propylene glycol and 1,3-propyleneglycol), butaneediol (e.g., 1,4-butaneediol), butaneediol (e.g.,1,3-butaneediol and 1,4-butenediol), butynediol, pentanediol (e.g.,1,5-pentanediol), hexanediol (e.g., 1,6-hexanediol), octanediol (e.g.,1,8-octanediol), neopentyl glycol, 2-methyl-1,3-propanediol, diethyleneglycol, triethylene glycol, tetraethylene glycol, dipropylene glycol anddibutylene glycol.

In one or more embodiments, the polar solvent contains a triol (acompound that contains three hydroxy groups in its molecular structure),such as glycerin and 1,2,6-Hexanetriol.

Other non-limiting examples of polar solvents include pyrrolidones,(such as N-methyl-2-pyrrolidone and 1-methyl-2-pyrrolidinone), dimethylisosorbide, 1,2,6-hexapetriol, dimethyl sulfoxide (DMSO), ethylproxitol, dimethylacetamide (DMAc) and alpha hydroxy acids, such aslactic acid and glycolic acid.

According to still other embodiments, the polar solvent is apolyethylene glycol (PEG) or PEG derivative that is liquid at ambienttemperature, including PEG200 (MW (molecular weight) about 190-210 kD),PEG300 (MW about 285-315 kD), PEG400 (MW about 380-420 kD), PEG600 (MWabout 570-630 kD) and higher MW PEGs such as PEG 4000, PEG 6000 and PEG10000 and mixtures thereof.

Polar solvents are known to enhance the penetration of active agent intothe skin and through the skin, and therefore, their inclusion in thecomposition of the present invention can be desirable, despite theirundesirable skin drying and irritation potential. There is at one levela commonality between the different polar solvents and their penetrationenhancement properties. Lower molecular weight alcohols can sometimes bemore potent as a solvent, for example by extracting lipids from the skinlayers more effectively, which characteristic can adversely affect theskin structure and cause dryness and irritation. Therefore the selectionof lower molecular weight alcohols is ideally avoided.

Polar solvents, such as detailed below possess high solubilizingcapacity and contribute to the skin penetration of an active agent. Nonlimiting examples include dimethyl isosorbide polyols, such as glycerol(glycerin), propylene glycol, hexylene glycol, diethylene glycol,propylene glycol n-alkanols, terpenes, di-terpenes, tri-terpenes,limonene, terpene-ol, 1-menthol, dioxolane, ethylene glycol, otherglycols, oleyl alcohol, alpha-hydroxy acids, such as lactic acid andglycolic acid, sulfoxides, such as dimethylsulfoxide (DMSO),dimethylformanide, methyl dodecyl sulfoxide, dimethylacetamide, azone(1-dodecylazacycloheptan-2-one), 2-(n-nonyl)-1,3-dioxolane, alkanols,such as dialkylamino acetates, and admixtures thereof. In certainpreferred embodiments, the polar solvent is selected from the groupconsisting of dimethyl isosorbide glycerol (glycerin), propylene glycol,hexylene glycol, terpene-ol, oleyl alcohol, lactic acid and glycolicacid.

Skin Penetration Enhancer

A “skin penetration enhancer”, also termed herein “penetrationenhancer,” is an organic solvent, typically soluble in both water andoil. Examples of penetration enhancer include polyols, such as glycerol(glycerin), propylene glycol, hexylene glycol, diethylene glycol,propylene glycol n-alkanols, terpenes, di-terpenes, tri-terpenes,terpen-ols, limonene, terpene-ol, 1-menthol, dioxolane, ethylene glycol,hexylene glycol, other glycols, sulfoxides, such as dimethylsulfoxide(DMSO), dimethylformanide, methyl dodecyl sulfoxide, dimethylacetamide,dimethylisosorbide, monooleate of ethoxylated glycerides (with 8 to 10ethylene oxide units), azone (1-dodecylazacycloheptan-2-one),2-(n-nonyl)-1,3-dioxolane, esters, such as isopropylmyristate/palmitate, ethyl acetate, butyl acetate, methyl proprionate,capric/caprylic triglycerides, octylmyristate, dodecyl-myristate;myristyl alcohol, lauryl alcohol, lauric acid, lauryl lactate ketones;amides, such as acetamide oleates such as triolein; various alkanoicacids such as caprylic acid; lactam compounds, such as azone; alkanols,such as dialkylamino acetates, and admixtures thereof.

According to one or more embodiments, the penetration enhancer is apolyethylene glycol (PEG) or PEG derivative that is liquid at ambienttemperature

Potent Solvent

In one or more embodiments of the present invention, the foamablecomposition includes a potent solvent, in addition to or in place of oneof the hydrophobic solvents, polar solvents or emollients of thecomposition. A potent solvent is a solvent other than mineral oil thatsolubilizes a specific active agent substantially better than ahydrocarbon solvent such as mineral oil or petrolatum. For example, apotent solvent solubilizes the active agent 5 fold better than ahydrocarbon solvent; or even solubilizes the active agent 10-fold betterthan a hydrocarbon solvent.

In one or more embodiments of the present invention, the compositionincludes at least one active agent in a therapeutically effectiveconcentration; and at least one potent solvent in a sufficient amount tosubstantially solubilize the at least one active agent in thecomposition. The term “substantially soluble” means that at least 95% ofthe active agent has been solubilized, i.e., 5% or less of the activeagent is present in a solid state. In one or more embodiments, theconcentration of the at least one potent solvent is more than about 40%of the at least one solvent of the composition of the present invention;or even more than about 60%.

Non-limiting examples of pairs of active agent and potent solventinclude: Betamethasone valerate: Practically insoluble in mineral oil(<0.01%); soluble more than 1% in glycofurol; Hydrocortisone butyrate:Practically insoluble in mineral oil (<0.01%); soluble more than 1% inglycofurol; Metronidazole: Practically insoluble in mineral oil(<0.01%); soluble more than 1% in dimethyl isosrbide; Ketoconazole:Practically insoluble in mineral oil (<0.01%); soluble more than 1% inglycofurol, propylene glycol and dimethyl isosrbide; Mupirocin:Practically insoluble in mineral oil (<0.01%); soluble more than 1% inglycofurol, hexylene glycol, dimethyl isosorbide, propylene glycol andpolyethylene glycol 400 (PEG 400); Meloxicam, a nonsteroidalanti-inflammatory agent: Practically insoluble in mineral oil (<0.001%);soluble in propylene glycol: 0.3 mg/mL; and in PEG 400: 3.7 mg/mL; andProgesterone: Practically insoluble in mineral oil (<0.001%); soluble inPEG 400: 15.3 mg/mL.

A non-limiting exemplary list of solvents that can be considered aspotent solvents includes polyethylene glycol, propylene glycol, hexyleneglycol, butaneediols and isomers thereof, glycerol, benzyl alcohol,DMSO, ethyl oleate, ethyl caprylate, diisopropyl adipate,dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone,polyvinylpyrrolidone, isosorbide derivatives, such as dimethylisosorbide, glycofurol and ethoxydiglycol (transcutol) and laurocapram.

The use of a potent solvent in a foam composition provides an improvedmethod of delivering poorly soluble therapeutic agents to a target area.It is known that low drug solubility results in poor bioavailability,leading to decreased effectiveness of treatment. Foam compositions ofthe present invention, for which the solvent includes a potent solvent,increase the levels of the active agent in solution and thus, providehigh delivery and improved therapy.

Potent solvents, as defined herein, are usually liquid. Formulationscomprising potent solvents and active agents are generallydisadvantageous as therapeutics, since their usage involves unwanteddripping and inconvenient method of application; resulting in inadequatedosing. Surprisingly, the foams of the present invention, which aredrip-free, provide a superior vehicle for such active agents, enablingconvenient usage and accurate effective dosing.

In one or more embodiments of the present invention the presentinvention the foamable pharmaceutical composition may additionallyinclude a mixture of two or more of the solvents selected from the groupof hydrophobic solvents, silicone oils, emollients, polar solvents andpotent solvents in an appropriate proportion as would be appreciated toa person skilled in the art.

In one or more embodiments of the present invention, the PPG alkyl ethermay act as a potent solvent

Additional Components

In an embodiment of the present invention, a composition of the presentinvention includes one or more additional components. Such additionalcomponents include but are not limited to anti perspirants, anti-staticagents, buffering agents, bulking agents, chelating agents, cleansers,colorants, conditioners, deodorants, diluents, dyes, emollients,fragrances, hair conditioners, humectants, pearlescent aids, perfumingagents, permeation enhancers, pH-adjusting agents, preservatives,protectants, skin penetration enhancers, softeners, solubilizers,sunscreens, sun blocking agents, sunless tanning agents, viscositymodifiers and vitamins. As is known to one skilled in the art, in someinstances a specific additional component may have more than oneactivity, function or effect.

Propellants

Suitable propellants include volatile hydrocarbons such as butane,propane, isobutane and fluorocarbon gases, or mixtures thereof.

The propellant makes up about 5-25 wt % of the foamable composition. Thepropellants are used to generate and administer the foamable compositionas a foam. The total composition including propellant, foamablecompositions and optional ingredients is referred to as the foamablecomposition.

Alcohol and organic solvents render foams inflammable. It has beensurprisingly discovered that fluorohydrocarbon propellants, other thanchloro-fluoro carbons (CMOs), which are non-ozone-depleting propellants,are particularly useful in the production of a non-flammable foamablecomposition. A test according to European Standard prEN 14851, titled“Aerosol containers—Aerosol foam flammability test” revealed thatcompositions containing an organic carrier that contains a hydrophobicorganic carrier and/or a polar solvent, which are detected asinflammable when a hydrocarbon propellant is used, become non-flammable,while the propellant is an HFC propellant.

Such propellants include, but are not limited to, hydrofluorocarbon(HFC) propellants, which contain no chlorine atoms, and as such, fallcompletely outside concerns about stratospheric ozone destruction bychlorofluorocarbons or other chlorinated hydrocarbons. Exemplarynon-flammable propellants according to this aspect of the inventioninclude propellants made by DuPont under the registered trademark Dymel,such as 1,1,1,2 tetrafluorethane (Dymel 134), and 1,1,1,2,3,3,3heptafluoropropane (Dymel 227). HFCs possess Ozone Depletion Potentialof 0.00 and thus, they are allowed for use as propellant in aerosolproducts.

Notably, the stability of foamable emulsions including HFC as thepropellant can be improved in comparison with the same composition madewith a hydrocarbon propellant.

In one or more embodiments foamable compositions comprise a combinationof a HFC and a hydrocarbon propellant such as n-butanee or mixtures ofhydrocarbom propellants such as propane, ispbutane and butane.

Microemulsions and Nanoemulsions

Microemulsions and nanoemulsion are monophasic, transparent (or slightlytranslucent) dispersions of oil and water. Unlike conventionalemulsions, microemulsions and nanoemulsion are thermodynamically stable,making them a favorable vehicle for pharmaceutical compositions, whichhave to maintain stability for long periods of time. They and a methodof manufacture are more particularly described in US2006/0233721 whichis incorporated herein by way of reference. As will be appreciated by aman of the art the methodology may be adapted according to the type ofcarrier composition.

Aging

In order to project the potential shelf life and stability of thecompositions and their ingredients particularly active or benefit agentsthe compositions can subjected to a number of tests, includingcentrifugation to look for resistance to creaming, phase separation; oneor more freeze thaw cycles, standing at room and higher temperatures asan indicator of resistance to aging.

Composition and Foam Physical Characteristics and Advantages

A pharmaceutical or cosmetic composition manufactured using the foamablecarrier of the present invention is very easy to use. When applied ontothe afflicted body surface of mammals, i.e., humans or animals, it is ina foam state, allowing free application without spillage. Upon furtherapplication of a mechanical force, e.g., by rubbing the composition ontothe body surface, it freely spreads on the surface and is rapidlyabsorbed.

The foamable composition of the present invention is stable, having anacceptable shelf-life of at least one year, or preferably, at least twoyears at ambient temperature, as revealed in accelerated stabilitytests. The foamable compositions according to the present invention arestable. Following accelerated stability studies, they demonstratedesirable texture; they form fine bubble structures that do not breakimmediately upon contact with a surface, spread easily on the treatedarea and absorb quickly.

The composition should also be free flowing, to allow it to flow throughthe aperture of the container, e.g., and aerosol container, and createan acceptable foam.

Foam quality can be graded as follows:

Grade E (excellent): very rich and creamy in appearance, does not showany bubble structure or shows a very fine (small) bubble structure; doesnot rapidly become dull; upon spreading on the skin, the foam retainsthe creaminess property and does not appear watery.

Grade G (good): rich and creamy in appearance, very small bubble size,“dulls” more rapidly than an excellent foam, retains creaminess uponspreading on the skin, and does not become watery.

Grade FG (fairly good): a moderate amount of creaminess noticeable,bubble structure is noticeable; upon spreading on the skin the productdulls rapidly and becomes somewhat lower in apparent viscosity.

Grade F (fair): very little creaminess noticeable, larger bubblestructure than a “fairly good” foam, upon spreading on the skin itbecomes thin in appearance and watery.

Grade P (poor): no creaminess noticeable, large bubble structure, andwhen spread on the skin it becomes very thin and watery in appearance.

Grade VP (very poor): dry foam, large very dull bubbles, difficult tospread on the skin.

Topically administrable foams are typically of quality grade E or G,when released from the aerosol container. Smaller bubbles are indicativeof more stable foam, which does not collapse spontaneously immediatelyupon discharge from the container. The finer foam structure looks andfeels smoother, thus increasing its usability and appeal.

As further aspect of the foam is breakability. The breakable foam isthermally stable, yet breaks under sheer force. Sheer-force breakabilityof the foam is clearly advantageous over thermally induced breakability.Thermally sensitive foams immediately collapse upon exposure to skintemperature and, therefore, cannot be applied on the hand and afterwardsdelivered to the afflicted area.

Another property of the foam is specific gravity, as measured uponrelease from the aerosol can. Typically, foams have specific gravity ofless than 0.12 g/mL; or less than 0.10 g/mL; or less than 0.08 g/mL,depending on their composition and on the propellant concentration.

Pharmaceutical Composition

The foamable carrier of the present invention is an ideal vehicle foractive pharmaceutical ingredients and active cosmetic ingredients. Inthe context of the present invention, active pharmaceutical ingredientsand active cosmetic ingredients are collectively termed “active agent”or “active agents.”

In one or more embodiments, the dicarboxylic acid or dicarboxylic esteris the active ingredient. It can be used in the formulation as asuspended solid or in solution, alone or in combination with otheractive agents. As is known to one skilled in the art, in some instancesa specific active agent may have more than one activity, function oreffect.

In one embodiment, the dicarboxylic acid or dicarboxylic acid ester isuseful as an antibiotic, an antifungal agent, a keratolytic agent, aninhibitor of the reduction of testosterone to dihydrotestosterone, aninhibitor of the production of sebum in the sebaceous gland, ananti-acne agent, by way of example. Dicarboxylic acids, and azxelaicacid in particular, may be used for the treatment of diaper rash,hyperpigmentary drmatoses, acne, presbyderma of aging skin,hyperhydrosis, ischthyosis, and wrinkling of the skin, anti-tumor agents(for example, in conjunction with vitamins A, E and D), rosacea, apigmentation disorder, a cell proliferation abnormality a skin infectionand a skin inflammation and treatment of corns and callouses due to theanti-keratolytic effects.

In one or more embodiments, the dicarboxylic acid or dicarboxylic esteris used as a solvent for an active agent or as a penetration enhancerfor an active agent.

Suitable active agents for use in conjunction with a dicarboxylic acidor a dicarboxylic ester include, but are not limited to, active herbalextracts, acaricides, age spot and keratose removing agents, allergen,analgesics, local anesthetics, antiacne agents, antiallergic agents,antiaging agents, antibacterials, antibiotics, antiburn agents,anticancer agents, antidandruff agents, antidepressants, antidermatitisagents, antiedemics, antihistamines, antihelminths, antihyperkeratolyteagents, antiinflammatory agents, antiirritants, antilipemics,antimicrobials, antimycotics, antiproliferative agents, antioxidants,anti-wrinkle agents, antipruritics, antipsoriatic agents, antirosaceaagents antiseborrheic agents, antiseptic, antiswelling agents, antiviralagents, antiyeast agents, astringents, topical cardiovascular agents,chemotherapeutic agents, corticosteroids, dicarboxylic acids,disinfectants, fungicides, hair growth regulators, hormones, hydroxyacids, immunosuppressants, immunoregulating agents, insecticides, insectrepellents, keratolytic agents, lactams, metals, metal oxides,mitocides, neuropeptides, non-steroidal anti-inflammatory agents,oxidizing agents, pediculicides, photodynamic therapy agents, retinoids,sanatives, scabicides, self tanning agents, skin whitening agents,vasoconstrictors, vasodilators, vitamins, vitamin D derivatives, woundhealing agents and wart removers. As is known to one skilled in the art,in some instances a specific active agent may have more than oneactivity, function or effect.

In one or more embodiments, the formulation additionally includes asteroidal anti-inflammatory agent. The dicarboxylic acid ester ispresent in the composition in an amount sufficient to solubilize thesteroid. Exemplary steroidal anti-inflammatory agents include, but arenot limited to, corticosteroids such as bydrocortisone,hydroxyltriamcinolone, alpha-methyl dexamethasone,dexamethasone-phosphate, beclomethsone dipropionate, clobetasolvalemate, desonide, desoxymethasone, desoxycorticosterone acetate,dexamethasone, dichlorisone, diflorasone diacetate, diflucortolonevalerate, fluadrenolone, fluclorolone acetonide, fludrocortisone,flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortinebutylester, fluocortolone, fluprednidene (fluprednylidene) acetate,flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisonebutyrate, methylprednisolone, triamcinolone acetonide, cortisone,cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate,fluradrenolone acetonide, medrysone, amcinafel, amcinafide,betamethasone and the balance of its esters, chloroprednisone,chlorprednisone acetate, clocortelone, clescinolone, dichlorisone,difluprednate, flucloronide, flunisolide, fluoromethalone, fluperolone,fluprednisolone, hydrocortisone valerate, hydrocortisonecyclopentylpropionate, hydrocortmate, mepreddisone, paramethasone,prednisolone, prednisone, beclomethasone dipropionate, triamcinolone,and mixtures thereof. In an embodiment of the present invention, thedicarboxylic acid ester is present in the composition in an amountsufficient to solubilize the steroid.

In one embodiment, the formulation additionally includes animmunomodulator. The dicarboxylic acid ester is present in thecomposition in an amount sufficient to solubilize the immunomodulator.Immunomodulators are chemically or biologically-derived agents thatmodify the immune response or the functioning of the immune system (asby the stimulation of antibody formation or the inhibition of whiteblood cell activity). Immunomodulators include, among other options,cyclic peptides, such as cyclosporine, tacrolimus, tresperimus,pimecrolimus, sirolimus (rapamycin), verolimus, laflunimus, laquinimodand imiquimod. Such compounds, delivered in the foam of the presentinvention, are especially advantageous in skin disorders such aspsoriasis, eczema and atopic dermatitis, where the large skin areas areto be treated.

In an embodiment of the present invention, the active agent is selectedfrom a dicarboxylic acid and a dicarboxylic acid ester.

Because of the multiple therapeutic properties of dicarboxylic acids andtheir respective esters, the combination of such dicarboxylic acids ortheir respective esters with another active agents can result in asynergistic therapeutic benefit. For example, psoriasis is characterizedby a heperkeratinization aspect and an inflammation, and therefore, itstreatment can benefit from the combination of a dicarboxylic acid, whichis keratolytic and a steroid.

Fields of Applications

The foamable carrier of the present invention is suitable for treatingany inflicted surface. In one or more embodiments, foamable carrier issuitable for administration to the skin, a body surface, a body cavityor mucosal surface, e.g., the cavity and/or the mucosa of the nose,mouth, eye, ear, respiratory system, vagina or rectum (severally andinterchangeably termed herein “target site”).

In one embodiment, the disorder is a dermatological disorder, which canbe treated by a dicarboxylic acid.

In another embodiment, the disorder is a dermatological disorder thatbenefits from the use of a dicarboxylic acid or dicarboxylic ester inconjunction with another active agent. The dicarboxylic acid ordicarboxylic ester may benefit by improving the solubility of the activeagent or increasing the penetration of the active agent. Thedicarboxylic acid or dicarboxylic ester may also provide a synergistictherapeutic effect in combination with the active agent.

By selecting a suitable active agent, or a combination of two or moreactive agents, the foamable composition of the present invention isuseful in treating an animal or a human patient having any one of avariety of dermatological disorders, including dermatological pain,dermatological inflammation, acne, acne vulgaris, inflammatory acne,non-inflammatory acne, acne fulminans, nodular papulopustular acne, acneconglobata, dermatitis, bacterial skin infections, fungal skininfections, viral skin infections, parasitic skin infections, skinneoplasia, skin neoplasms, pruritis, cellulitis, acute lymphangitis,lymphadenitis, erysipelas, cutaneous abscesses, necrotizing subcutaneousinfections, scalded skin syndrome, folliculitis, furuncles, hidradenitissuppurativa, carbuncles, paronychial infections, rashes, erythrasma,impetigo, ecthyma, yeast skin infections, warts, molluscum contagiosum,trauma or injury to the skin, post-operative or post-surgical skinconditions, scabies, pediculosis, creeping eruption, eczemas, psoriasis,pityriasis rosea, lichen planus, pityriasis rubra pilaris, edematous,erythema multiforme, erythema nodosum, granuloma annulare, epidermalnecrolysis, sunburn, photosensitivity, pemphigus, bullous pemphigoid,dermatitis herpetiformis, keratosis pilaris, callouses, corns,ichthyosis, skin ulcers, ischemic necrosis, miliaria, hyperhidrosis,moles, Kaposi's sarcoma, melanoma, malignant melanoma, basal cellcarcinoma, squamous cell carcinoma, poison ivy, poison oak, contactdermatitis, atopic dermatitis, rosacea, purpura, moniliasis,candidiasis, baldness, alopecia, Behcet's syndrome, cholesteatoma,Dercum disease, ectodermal dysplasia, gustatory sweating, nail patellasyndrome, lupus, hives, hair loss, Hailey-Hailey disease, chemical orthermal skin burns, scleroderma, aging skin, wrinkles, sun spots,necrotizing fasciitis, necrotizing myositis, gangrene, scarring, andvitiligo.

Likewise, the foamable composition of the present invention is suitablefor treating a disorder of a body cavity or mucosal surface, e.g., themucosa of the nose, mouth, eye, ear, respiratory system, vagina orrectum. Non limiting examples of such conditions include chlamydiainfection, gonorrhea infection, hepatitis B, herpes, HIV/AIDS, humanpapillomavirus (HPV), genital warts, bacterial vaginosis, candidiasis,chancroid, granuloma Inguinale, lymphogranuloma venereum, mucopurulentcervicitis (MPC), molluscum contagiosum, nongonococcal urethritis (NGU),trichomoniasis, vulvar disorders, vulvodynia, vulvar pain, yeastinfection, vulvar dystrophy, vulvar intraepithelial neoplasia (VIN),contact dermatitis, pelvic inflammation, endometritis, salpingitis,oophoritis, genital cancer, cancer of the cervix, cancer of the vulva,cancer of the vagina, vaginal dryness, dyspareunia, anal and rectaldisease, anal abscess/fistula, anal cancer, anal fissure, anal warts,Crohn's disease, hemorrhoids, anal itch, pruritus ani, fecalincontinence, constipation, polyps of the colon and rectum.

In an embodiment of the present invention, the disorder is adermatological disorder, which can be treated by a dicarboxylic acid.

In an embodiment of the present invention, the disorder is adermatological disorder, which can be treated by a dicarboxylic acidester.

In an embodiment of the present invention, the disorder is adermatological disorder, which can be treated by a topical steroid, andthe dicarboxylic acid or dicarboxylic ester provides a beneficial effectby increasing the solubility or penetration of the topical steroid.

In an embodiment of the present invention, the disorder is adermatological disorder, which can be treated by an immunomodulator andthe dicarboxylic acid or dicarboxylic ester provides a beneficial effectby increasing the solubility or penetration of the topicalimmunomodulator.

In an embodiment of the present invention, the disorder is adermatological disorder, which can be treated by an anti-infectiveagent, such as an antibacterial agent, and antibiotic, an antifungalagent and an antiviral agent, and the dicarboxylic acid or dicarboxylicester provides a beneficial effect as an anti-infective agent or byincreasing the solubility or penetration of the anti-infective agent.

In an embodiment of the present invention, the disorder is adermatological disorder, which is common in children. Foam isadvantageous in the topical treatment of children, who are sensitive totreatment with a cream or ointment.

In an embodiment of the present invention, the disorder is atopicdermatitis and the active agent is a steroid, further including adicarboxylic acid (DCA) or DCA ester to stabilize or solubilize thetopical steroid.

In an embodiment of the present invention, the disorder is psoriasis andthe active agent is a steroid, further including a DCA or DCA ester tostabilize or solubilize the topical steroid.

In an embodiment of the present invention, the disorder is selected frompsoriasis and atopic dermatitis and the active agent comprises a steroidand an additional non-steroidal active agent, such as a vitamin Dderivative, further including a DCA or DCA ester to stabilize orsolubilize the topical steroid and/or non-steroidal active agent.

In an embodiment of the present invention, the disorder is selected frompsoriasis and atopic dermatitis and the active agent comprises animmunomodulator, further including a DCA or DCA ester to stabilize orsolubilize the immunomodulator.

In an embodiment of the present invention, the composition is useful forthe treatment of an infection. In one or more embodiments, thecomposition is suitable for the treatment of an infection, selected fromthe group of a bacterial infection, a fungal infection, a yeastinfection, a viral infection and a parasitic infection.

In an embodiment of the present invention, the composition is useful forthe treatment of wound, ulcer and burn.

The composition of the present invention is also suitable foradministering a hormone to the skin or to a mucosal membrane or to abody cavity, in order to deliver the hormone into the tissue of thetarget organ, in any disorder that responds to treatment with a hormone.

Other foamable compositions are described in: U.S. Publication No.05-0232869, published on Oct. 20, 2005, entitled NONSTEROIDALIMMUNOMODULATING KIT AND COMPOSITION AND USES THEREOF; U.S. PublicationNo. 05-0205086, published on Sep. 22, 2005, entitled RETINOIDIMMUNOMODULATING KIT AND COMPOSITION AND USES THEREOF; U.S. PublicationNo. 06-0018937, published on Jan. 26, 2006, entitled STEROID KIT ANDFOAMABLE COMPOSITION AND USES THEREOF; U.S. Publication No. 05-0271596,published on Dec. 8, 2005, entitled VASOACTIVE KIT AND COMPOSITION ANDUSES THEREOF; U.S. Publication No. 06-0269485, published on Nov. 30,2006, entitled ANTIBIOTIC KIT AND COMPOSITION AND USES THEREOF; U.S.Publication No. 07-0020304, published on Jan. 25, 2007, entitledNON-FLAMMABLE INSECTICIDE COMPOSITION AND USES THEREOF; U.S. PublicationNo. 06-0193789, published on Aug. 31, 2006, entitled FILM FORMINGFOAMABLE COMPOSITION; U.S. patent application Ser. No. 11/732,547, filedon Apr. 4, 2007, entitled ANTI-INFECTION AUGMENTATION OF FOAMABLECOMPOSITIONS AND KIT AND USES THEREOF; U.S. Provisional PatentApplication No. 60/789,186, filed on Apr. 4, 2006, KERATOLYTICANTIFUNGAL FOAM; U.S. Provisional Patent Application No. 0/815948, filedon Jun. 23, 2006, entitled FOAMABLE COMPOSITIONS COMPRISING A CALCIUMCHANNEL BLOCKER, A CHOLINERGIC AGENT AND A NITRIC OXIDE DONOR; U.S.Provisional Patent Application No. 60/818,634, filed on Jul. 5, 2006,entitled DICARBOXYLIC ACID FOAMABLE VEHICLE AND PHARMACEUTICALCOMPOSITIONS THEREOF; U.S. Provisional Patent Application No.60/843,140, filed on Sep. 8, 2006, entitled FOAMABLE VEHICLE AND VITAMINPHARMACEUTICAL COMPOSITIONS THEREOF, all of which are incorporatedherein by reference in their entirety. More particularly any of theactive ingredients; the solvents; the surfactants; foam adjuvants;penetration enhancers; humectants; moisturizers; and other excipients aswell as the propellants listed therein can be applied herein and areincorporated by reference.

The following examples further exemplify the benefit agent foamablepharmaceutical carriers, pharmaceutical compositions thereof, methodsfor preparing the same, and therapeutic uses of the compositions. Theexamples are for the purposes of illustration only and are not intendedto be limiting of the invention. Many variations may be carried out byone of ordinary skill in the art and are contemplated within the fullscope of the present invention.

Methodology

A general procedure for preparing foamable compositions is set out in WO2004/037225, which is incorporated herein by reference.

Emulsion Foam

-   -   1. Mix oily phase ingredients and heat to 75° C. to melt all        ingredients and obtain homogeneous mixture.    -   2. Mix polymers in water with heating or cooling as appropriate        for specific polymer.    -   3. Add all other water soluble ingredients to water-polymer        solution and heat to 75° C.    -   4. Add slowly internal phase to external phase at 75° C. under        vigorous mixing and homogenize to obtain fine emulsion.        Alternatively the external phase is added slowly to the internal        phase.    -   5. Cool to below 40° C. and add sensitive ingredients with mild        mixing.    -   6. Cool to room temperature.        Waterless Foam    -   1. Dissolve the polymers in the main solvent with heating or        cooling as appropriate for specific polymer. Add the all other        ingredients and heat to 75° C. to melt and dissolve the various        ingredients.    -   2. Cool to below 40° C. and add sensitive ingredients with mild        mixing.    -   3. Cool to room temperature.        Oily Waterless Foam    -   1. Mix all ingredients excluding polymers and heat to 75° C. to        melt and dissolve and obtain homogeneous mixture.    -   2. Mix well and cool to below 40° C. and add the polymers and        sensitive ingredients with moderate mixing.    -   3. Cool to room temperature.        Oily Foam with Phospholipids and/or Water    -   1. Swell the phospholipids in the main oily solvent under mixing        for at least 20 minutes until uniform suspension is obtained.    -   2. Add all other ingredients excluding polymers and heat to        75° C. to melt and dissolve and obtain homogeneous mixture.    -   3. Mix well and cool to below 40° C. and add the polymers and        sensitive ingredients with moderate mixing.    -   4. Cool to room temperature.    -   5. In case of polymers dissolved in water or organic solvent,        dissolve the polymers in the solvent with heating or cooling as        appropriate for specific polymer and add to the oily mixture        under vigorous mixing at ˜40° C.        Canisters Filling and Crimping

Each aerosol canister is filled with PFF and crimped with valve usingvacuum crimping machine.

Pressurizing

Propellant Filling

-   -   Pressurizing is carried out using a hydrocarbon gas or gas        mixture    -   Canisters are filled and then warmed for 30 sec in a warm bath        at 50° C. and well shaken immediately thereafter.

Closure Integrity Test.

-   -   Each pressurized canister is subjected to bubble and crimping        integrity testing by immersing the canister in a 60° C. water        bath for 2 minutes. Canisters are observed for leakage as        determined by the generation of bubbles. Canisters releasing        bubbles are rejected.        Tests

By way of non limiting example the objectives of hardness, collapse timeand FTC stability tests are briefly set out below as would beappreciated by a person of the art.

Hardness

LFRA100 instrument is used to characterize hardness. A probe is insertedinto the test material. The resistance of the material to compression ismeasured by a calibrated load cell and reported in units of grams on thetexture analyzer instrument display. Preferably at least three repeattests are made. The textural characteristics of a dispensed foam caneffect the degree of dermal penetration, efficacy, spreadability andacceptability to the user. The results can also be looked at as anindicator of softness. Note: the foam sample is dispensed into analuminum sample holder and filled to the top of the holder.

Collapse Time

Collapse time (CT) is examined by dispensing a given quantity of foamand photographing sequentially its appearance with time duringincubation at 36° C. It is useful for evaluating foam products, whichmaintain structural stability at skin temperature for at least 1 min.

Viscosity

Viscosity is measured with Brookfield LVDV-II+PRO with spindle SC4-25 atambient temperature and 10, 5 and 1 RPM. Viscosity is usually measuredat 10 RPM. However, at about the apparent upper limit for the spindle of˜>50,000 CP, the viscosity at 1 RPM may be measured, although thefigures are of a higher magnitude.

FTC (Freeze Thaw Cycles)

To check the foam appearance under extreme conditions of repeated cyclesof cooling, heating, (first cycle) cooling, heating (second cycle) etc.,commencing with −100° C. (24 hours) followed by +400° C. (24 hours)measuring the appearance and again repeating the cycle for up to threetimes.

Creaming by Centrifugation:

1. Principle of Test

-   -   The centrifugation used in this procedure serves as a stress        condition simulating the aging of the liquid dispersion under        investigation. Under these conditions, the centrifugal force        applied facilitates the coalescence of dispersed globules or        sedimentation of dispersed solids, resulting in loss of the        desired properties of the formulated dispersion.        2. Procedure    -   2.1. Following preparation of the experimental formulation/s,        allow to stand at room temperature for ≥24 h.    -   2.2. Handle pentane in the chemical hood. Add to each        experimental formulation in a 20-mL glass vial a quantity of        pentane equivalent to the specified quantity of propellant for        that formulation, mix and allow formulation to stand for at        least 1 h and not more than 24 h.    -   2.3. Transfer each mixture to 1.5 mL microtubes. Tap each        microtube on the table surface to remove entrapped air bubbles.    -   2.4. Place visually balanced microtubes in the centrifuge rotor        and operate the centrifuge at 3,000 rpm for 10 min or at 1,000        rpm for 10 min.

Intra-Canister Uniformity

-   -   1. Representative product containers are collected, sample test        solutions are prepared and the content of the analyte is        determined according to standard methods in the art. Variability        of content is characterized as percent difference or relative        standard deviation, as appropriate, according to the number of        samples evaluated.    -   2. The results ascertain variability or uniformity within a        given container in content of analytes (primarily active        pharmaceutical ingredients, but also preservatives) taken from        different parts of a pressurized canister drug products    -   3. Two full canisters were shaken according to product        instructions. About 1-3 g of Foam was dispensed from each        canister and discarded. Foam sufficient for two replicate sample        solution preparations was then dispensed into a glass beaker.        This represents the initial sample. A middle portion is then        dispensed from each canister being about half the canister        contents. This middle dispensed portion may be discarded or        collected for testing purposes, as necessary. Foam sufficient        for two replicate sample solution preparations was then        dispensed into a glass beaker. This represents the final sample.        A small amount of formulation remains in the canister. The foam        samples were stirred to remove gas/air bubbles. From both the        initial and final foam portions from each canister 4 separate        sample solutions are prepared and analyzed, 2 from the initial        portion and 2 from the final portion. The percent difference is        calculated as follows:

$\frac{\begin{matrix}{{{Difference}\mspace{14mu}{between}\mspace{14mu}{content}\mspace{14mu}{determined}}\mspace{14mu}} \\{{{{in}\mspace{14mu}{initial}}\mspace{14mu}\&}\mspace{14mu}{final}\mspace{14mu}{portions}}\end{matrix}\mspace{14mu}}{{{{Mean}\mspace{14mu}{of}\mspace{14mu}{content}\mspace{14mu}{of}\mspace{14mu}{initial}}{\;\mspace{11mu}}\&}\mspace{14mu}{final}\mspace{14mu}{portions}} \times 100$

and the intra canister uniformity evaluated from the results.

Stock Compositions

Non-limiting examples of how stock solutions are made up with andwithout API. Other stock solutions may be made using the samemethodology by simply varying adding or omitting ingredients as would beappreciated by one of the ordinary skills in the art.

EXAMPLES

The invention is described with reference to the following examples.This invention is not limited to these examples and experiments. Manyvariations will suggest themselves and are within the full intendedscope of the appended claims.

Section A—Aqueous A1—Emollient Formulations A1—Example 1—VehicleComposition Containing Diisopropyl Adipate (DISPA)

The following foamable vehicles were prepared and the quality of theresultant foam was ascertained.

GOG GOG GOG GOG 08 09 10 11 PHASE Ingredient % w/w % w/w % w/w % w/w OilPhase (A) Capric/caprylic triglyceride 10.00 10.00 Diisopropyladipate(DISPA) 20.00 20.00 20.00 20.00 Benzyl alcohol 2.00 2.00 2.00 2.00 Oleylalcohol 20.00 20.00 10.00 10.00 PPG 15 stearyl ether 2.00 2.00 2.00 2.00Sorbitan laurate 1.50 Sorbitan stearate 4.00 4.00 2.00 2.00 Stearic acid4.00 4.00 2.00 Stearyl alcohol 3.00 Pemulen TR2 0.05 0.05 Water Phase(B) Hydroxypropyl methyl cellulose 0.15 Xanthan gum 0.15 Sucrose ester2.00 2.00 1.00 2.00 Propylene glycol 8.00 8.00 8.00 8.00 Glycerin 5.005.00 5.00 8.00 TEA 0.10 0.10 0.10 Water 37.85 32.90 37.85 31.20 Foamquality E E G E Emulsion stability (10000 RPM) Stable Stable StableStable

Notes:

-   -   Compositions GOG 08 and GOG 09 contain 20% DISPA and 20% oleyl        alcohol to provide (1) high emolliency; (2) high solubilizing        capacity of an oil-soluble active agent; and (3) enhanced skin        delivery of an active agent.    -   Compositions GOG 10 and GOG 11 contain 20% DISPA, 20% oleyl        alcohol and 10% capric/caprylic triglyceride to provide (1)        enhanced emolliency; (2) high solubilizing capacity of an        oil-soluble active agent; and (3) enhanced skin delivery of an        active agent.    -   The compositions contain about 30% water. Therefore, they        provide high skin barrier build-up effect.    -   The compositions are oil in water emulsions, despite the fact        that there is oil more than water in the formulation. Oil in        water emulsion is maintained and stabilized by selecting a        surfactant that favors oil in water emulsions over water in oil        emulsions. Hence, the skin feeling of the composition is        favorable.    -   The surfactants, sorbitan laurate, sorbitan stearate and sucrose        esters, are POE-free and hence this formulation may be used with        active agents that are not compatible with POE.    -   The compositions can be used as lotions for topical therapy of        an inflammatory skin diorder.    -   In order to create a foamable composition, the composition is        filled into an aerosol canister and pressurized using a        liquefied or gas propellant can be added at a concentration of        about 3% to about 25%.

A1—Example 2—Vehicle Composition Containing Diisopropyl Adipate (DISPA)

The following foamable vehicles were prepared and the quality of theresultant foam was ascertained.

GOG 13 GOG 14 GOG 15 PHASE Ingredient % w/w % w/w % w/w Oil Phase (A)Capric/caprylic 10.00 10.00 10.00 triglyceride Diisopropyladipate 20.00Dimethyl sebacate 20.00 Dioctyl malate 20.00 Benzyl alcohol 2.00 2.002.00 Oleyl alcohol 10.00 10.00 10.00 PPG 15 stearyl ether 2.00 2.00 2.00Sorbitan laurate 2.00 2.00 Sorbitan stearate 2.00 Stearic acid 1.20Stearyl alcohol 3.00 1.00 Water Hydroxypropyl 0.15 0.15 0.15 Phasemethyl cellulose Xanthan gum 0.15 0.15 0.15 Sucrose ester HLB 16 Sucroseester 3.00 2.00 2.00 HLB 11 Propylene glycol 17.70 17.70 17.70 GlycerinTEA 0.06 Water 30.00 33.00 32.74 Foam quality E G E Emulsion stabilityStable Stable Stable (10000 RPM)

Notes:

-   -   Composition GOG 13 contains 20% DISPA, 10% oleyl alcohol and 10%        capric/caprylic triglyceride, to provide (1) enhanced        emolliency; (2) high solubilizing capacity of an oil-soluble        active agent; and (3) enhanced skin delivery of an active agent.    -   Composition GOG 14 contains 20% dietthyl sebacate, 10% oleyl        alcohol and 10% capric/caprylic triglyceride, to provide (1)        enhanced emolliency; (2) high solubilizing capacity of an        oil-soluble active agent; and (3) enhanced skin delivery of an        active agent.    -   Composition GOG 15 contains 20% dioctyl malate, 10% oleyl        alcohol and 10% capric/caprylic triglyceride, to provide (1)        enhanced emolliency; (2) high solubilizing capacity of an        oil-soluble active agent; and (3) enhanced skin delivery of an        active agent.    -   The compositions contain about 30% water. Therefore, they        provide high skin barrier build-up effect    -   The compositions are oil in water emulsions, despite the fact        that there is oil more than water in the formulation. Hence, the        skin feeling of the composition is favorable.    -   The surfactants are POE-free: sorbitan laurate, sorbitan        stearate and sucrose esters.    -   The compositions can be used as lotions for topical therapy of        an inflammatory skin diorder.    -   In order to create a foamable composition, the composition is        filled into an aerosol canister and pressurized using a        liquefied or gas propellant can be added at a concentration of        about 3% to about 25%.

A1—Example 3—Vehicle Compositions Containing 10% to 50% DiisopropylAdipate (DISPA) as Solvent

The following foamable vehicles were prepared and the quality of theresultant foam was ascertained.

DCA001 DCA002 DCA003 DCA011 diisopropyl 10.00 20.00 30.00 40.00 adipate(DISPA) Steareth 2 3.06 3.67 4.89 4.89 Steareth 21 1.94 2.33 3.11 3.11Carboxy methyl 0.50 0.50 0.50 0.50 cellulose Water purified 84.50 73.5061.50 51.50 Total 100.00 100.00 100.00 100.00 Propellant 8.00 8.00 8.008.00 propane, isobutene and butane mixture Appearance: foam quality E EE E color White White White White odor No odor No odor No odor No odordensity 0.049 0.045 0.064 collapse time >300 >300 Hardness 18.76 31.77

Excellent foam formulations were prepared with DISPA, surfactant, and anominal amount of polymeric agent.

In foamable compositions using less than 40 wt % DISPA, no solvent otherthan water is required to make foamable composition with resultantexcellent foams. The use of a combination of ether-based or ester-basedsurfactants was found to be useful in forming excellent foams with aminimal number of ingredients. Without being bound by any particulartheory or mode of operation, it is believed that the use of non-ionicsurfactants with significant hydrophobic and hydrophilic components,increase the emulsifier or foam stabilization characteristics of thecomposition. Similarly, without being bound by any particular theory ormode of operation, using combinations of surfactants with high and lowHLB's to provide a relatively close packed surfactant layer maystrengthen the emulsion.

Visual test after addition of water indicated that DCA011 is an oil inwater emulsion.

A1—Example 4—Minimal Vehicle Compositions, Containing 40% DiisopropylAdipate (DISPA) with and without Polymer

The following foamable vehicles were prepared and the quality of theresultant foam was ascertained.

DCA011 DCA011A diisopropyl 40.00 40.00 adipate (DISPA) Steareth 2 4.894.89 Steareth 21 3.11 3.11 Carboxy methyl 0.50 cellulose Water purified51.50 52.00 Total 100.00 100.00 Propellant 8.00 8.00 propane, isobuteneand butane mixture Appearance: foam quality E E color White White odorNo odor No odor

Polymeric agents are introduced to improve foam. Surprisingly, it waspossible to prepare excellent foam formulations without a polymericagent from DISPA, surfactant, and water (and without a foam adjuvant oranother solvent). This is especially surprising as the use of water inthe composition is understood to benefit from the use of a polymericagent that can thicken or increase the viscosity of the compositions andimprove the resultant foam strength.

As in Example 3 and in Example 6, the combination of ether-based orester-based surfactants was found to be useful in forming excellentfoams with a minimal number of ingredients.

A1—Example 5—Vehicle Compositions Containing about 50% DiisopropylAdipate (DISPA) with Polymer

The following foamable vehicles were prepared and the quality of theresultant foam was ascertained.

DCA012 DCA013 diisopropyl adipate (DISPA) 46.00 50.00 Steareth 2 4.58Steareth 21 2.92 Isoceteth 20 3.00 Pemulen TR2 0.22 TEA 0.12 Carboxymethyl cellulose 0.50 Water purified 46.00 46.66 Total 100.00 100.00Propellant propane, isobutene and butane mixture 8.00 8.00 Appearance:foam quality E E color White White odor No odor No odor

-   -   Increasing the amount of DISPA above 46% resulted in a poor foam        and precipitation in formulations containing a polymer. Changing        the surfactant to GMS eliminated the precipitation but the foam        remained poor. Replacing the carboxy methyl cellulose polymeric        agent with carbopol did not result in any improvement.    -   Surprisingly, removal of the polymer at 50% DISPA, and steareth        21 and steareth 2 improved the foam quality but did not        eliminate the precipitation.    -   However, by changing the surfactants and polymeric agents it was        possible to increase the level of the DISPA and achieve        excellent foams without precipitation.    -   A combination of ether-based or ester-based surfactants was        found to be useful in forming excellent foams with a minimal        number of ingredients    -   It has been discovered also that by using a derivatized        hydrophilic polymer with hydrophobic alkyl moieties as a        polymeric emulsifier it is possible to stabilize the emulsion        better about or at the region of phase reversal tension. Other        types of derivatized polymers like silicone copolymers,        derivatized starch and derivatized dexrin may also a similar        stabilizing effect.

A1—Example 6—Vehicle Compositions Containing 60% Diisopropyl Adipate(DISPA) without Polymer

The following foamable vehicles were prepared and the quality of theresultant foam was ascertained.

DCA028 DCA029 DCA030 DCA031 diisopropyl adipate 60.00 60.00 diethylsebacate 60.00 60.00 Steareth 2 3.00 3.00 Steareth 21 2.00 2.00 PEG-40Stearate 4.00 4.00 Polysorbate 80 2.00 2.00 Water purified 34.00 34.0035.00 35.00 Total 100.00 100.00 100.00 100.00 Propellant (1681) 8.008.00 8.00 8.00 Appearance: foam quality E E E E color White White WhiteWhite odor No odor No odor No odor No odor 1000 rpm for 10 mins stablestable stable stable 3000 rpm for 10 mins % 80% 80% stable 75% creamingDCA 028-80% Creaming, 029-80% Creaming, 030-Homogenous, 031-75% Creamingat 3 K.

More surprisingly, by removal of the polymer and by reducing the levelsof steareth 21 and steareth 2 (ethers) (by about 40 to 50%) it waspossible to obtain excellent foams without precipitation at 60% DISPAand at 60% diethyl sebacate.

Without being bound to any particular theory the physical change in theformulation may be due to DISPA reaching a concentration where phasereversal from o/w to w/o emulsion is possible. Also at thisconcentration range of DISPA removal of the polymeric agent, whichitself can absorb water may—without being bound by any theory—haveresulted in additional water being available and perhaps reducinginternal emulsion tensions including any resulting from the presence ofthe polymeric agent and thereby unexpectedly resulting in improved foamquality even though polymeric agents are normally added to strengthenfoam quality. Also as the concentration of DISPA increased andconsequently the amount of water decreased it appears that the amount ofsurfactant required reduction as the external water phase is thinner.

It has also been discovered by using a different surfactant (ester basedin place of an ether based) system it was possible to achievecompositions that can generate good quality foam and withoutprecipitation with 60% DISPA or 60% diethyl sebacate in the absence ofpolymer. Addition of small amounts of xantham gum and methocel with 60%DISPA and the ester based surfactants resulted in poor foam.

It further appears to be the case that—without being limited by anytheory—for any given emulsion system as the oil phase is increased witha corresponding decrease in the water phase the internal tension orpressure for phase reversal will increase and the point at which thephase reversal can occur can be retarded by selective use of nontraditional derivatized polymeric agents with emulsifying properties,such as permulen that can stabilize the formulation and push back thepoint at which pressure for phase reversal might otherwise occur.

Surprisingly it was observed that more traditional polymeric agents likecarboxy methyl cellulose or carbopol or combinations like xantham gumand methocel can interfere with foam formulation at higher levels ofdicarboxylic esters.—all these formulations were examined byconductivity, by water addition test and by microscopic examination andwere found to be oil in water emulsions despite the fact that the amountof oil phase was approximately double that of the aqueous phase.

A1—Example 7—Vehicle Compositions Containing 10% to 45% Diethyl Sebacate

The following foamable vehicles were prepared and the quality of theresultant foam was ascertained.

DCA004 DCA005 DCA006 DCA024 DCA025 diethyl 10.00 20.00 30.00 40.00 45.00sebacate Steareth 2 4.00 5.00 5.33 6.00 6.00 Steareth 21 2.00 2.50 2.673.00 3.00 Carboxy 0.50 0.50 0.50 0.50 0.50 methyl cellulose Water 83.5072.00 61.50 50.50 45.50 purified Total 100.00 100.00 100.00 100.00100.00 Propellant 8.00 8.00 8.00 8.00 8.00 (1681) Appearance: foamquality E E E E E color White White White White White odor No odor Noodor No odor No odor No odor density 0.065 0.063 0.063 collapsetime >300 >300 >300 Hardness 17.23 24.67 27.39

Excellent foam formulations were prepared with diethyl sebacate,surfactant, a nominal amount of polymeric agent and water (and withoutany foam adjuvant or another solvent).

A1—Example 8—DISPA Formulation to Provide Stable Environment forPimecrolimus

Part 1—Composition of Placebo or Stock Formulation PIMF-001P

Material % w/w Caprylic/capric triglyceride 10.00 Diisopropyl adipate(DISPA) 20.00 Oleyl alcohol 10.00 PPG-15 stearyl ether 2.00 Stearic acid1.20 Sorbitan laurate 2.00 Benzyl alcohol 2.00 Methocel A4M(methylcellulose) 0.15 Xanthan gum 0.15 Sucrose stearic acid esters,mixture 2.00 Propylene glycol 17.70 Water purified 32.74 Trolamine (TEA)0.06 Total 100.00 Propellant 8.00

Pimecrolimus is sensitive to polyethylene glycol polymers so it wasnecessary to develop formulations with emulsifying agents other than forexample Twin, Myrj, or Brij surfactants, which are mainstreamsurfactants for pharmaceutical formulations. The combination of sorbitanlaurate with sucrose stearic acid esters was found to be effective.Pimecrolimus is insoluble in water but is soluble in DISPA.

Part 2—Pimecrolimus Content Determined by HPLC in PFF and FoamFormulation Samples at Various Times and Storage Conditions

The formulations were comprised of 98.8%; 98.6% and 98.4% stock plus1.2%, 1.4% and 1.6% pimecrolimus respectively.

14 days, 30 days, 50° C., 50° C. 30 days, glass 30 days, glass 50° C.Zero vials, 40° C., vials, canisters Sample name time PFF Foam PFF PFFPIM 1.2%: Result 1 1.12 1.14 1.22 1.05 1.13 batch PIMF001- Result 2 1.121.13 1.22 1.05 1.13 060620 Average 1.12 1.14 1.22 1.05 1.13 PIM 1.4%:Result 1 1.45 1.31 1.41 1.39 1.37 batch PIMF002- Result 2 1.41 1.33 1.411.39 1.37 060620 Average 1.41 1.32 1.41 1.39 1.37 PIM 1.6%: Result 11.58 1.5 1.59 1.56 1.55 batch PIMF003- Result 2 1.58 1.5 1.59 1.56 1.56060620 Average 1.58 1.5 1.59 1.56 1.56

As can be seen from the above there is no significant breakdown of theactive agent after a month when solubilized in DISPA.

Part 3—Physical Properties of PFF and Foam Preparations

PFF Formula Centrifugation, Centrifugation, Foam Appearance Name 3000rpm 10,000 rpm Quality Color Odor PIMF001 stable 80% creaming good whiteno odor PIMF002 stable stable good white no odor PIMF003 stable 95%creaming excellent white no odor

The basic formulation is a liquid emulsion which is inherently notstable with a tendency to cream or separate. Two contradictory forceshad to be overcome to produce a good to excellent stable foam. One is tohave a liquid formulation that stabilizes the active agent and the otheris to have a thick almost solid like constitution which resists orretards creaming and or separation. Nevertheless, by introducing intothe formulation a mixture of non-poly ethylene glycol polymersurfactants, which can produce a strong and closed packed barrierbetween the oil and the water that stabilizes the emulsion, togetherwith polymeric agents that retard creaming and or separation whilstmaintaining a fluid constitution, it was possible to stabilize the foamand active agent.

Microscopic examination disclosed that there were no crystals and thatPimecrolimus was solubilized.

A2—Suspensions A2—Example 9—Dicarboxylic Acid Composition

The following foamable vehicles were prepared and the quality of theresultant foam was ascertained.

Part A—Formulation

Ingredient % w/w Azelaic Acid 15.00 Water 51.90 Caprylic/Caprictriglyceride 10.87 Propylene glycol 10.87 Dimethyl isosorbide 5.44PEG-40 stearate 2.83 Cetostearyl alcohol 1.09 Polysorbate 80 0.98Glyceryl stearate 0.54 Xanthan gum 0.27 Methylcellulose A4M 0.11 Benzoicacid 0.10 NaOH (18% Solution) to pH = 4.5 Total: 100

Notes

-   -   The composition contains azelaic acid as a benefit agent, which        is suitable for treating a skin disorder, selected from acne,        rosacea, a pigmentation disorder, a cell proliferation        abnormality a skin infection and a skin inflammation.    -   The composition contains about 10% capric/caprylic triglyceride        to provide emolliency and about 10% propylene glycol and 10%        dimethyl isosorbide, to provide (1) enhanced emolliency; (2)        improved solubilizing capacity of the azelaic acid; and (3)        enhanced skin delivery.    -   The compositions contain about 50% water. Therefore, they        provide high skin barrier build-up effect.    -   The composition can be used as a cream/lotion for topical        therapy of a skin diorder.    -   In order to create a foamable composition, the composition is        filled into an aerosol canister and pressurized using a        liquefied or gas propellant can be added at a concentration of        about 3% to about 25%.        Part B—12 Month Stability Test

T-12 Test parameter T-0 upright inverted API* assay % amount of label99.3 100.5 101.7 by HPLC (%) % w/w 14.90 15.07 15.26 Product contentuniformity (Intra 1.79 0.10 0.88 canister) of API (%) *API = activepharmaceutical ingredient

The total amount of active agent at T-0 and at T-12 months as apercentage of 100% of ingredient that should be present according to thelabel and as a percentage in the formulation w/w, respectively wasdetermined. As can be seen, no reduction in API content was observedwithin the limits of detection and that the content remained uniform.The differences between samples taken from the top of the canisters andfrom samples taken from the bottom of the canisters were not significantand were well within the acceptable range.

Furthermore, the formulation comprising active ingredient azaleicacid—despite being a suspension and subject to graviational effect—wasable to withstand sedimentation and degredation such that it hasremained stable and uniformly distributed in the formulation as asuspension over a prolonged period of 12 months, whilst remainingflowable and shakable.

Example 10—Additional Dicarboxylic Acid Compositions

The following foamable vehicles were prepared and the quality of theresultant foam was ascertained.

Formulation: AZL018 AZL034 AZL035 AZL036 AZL037 AZL038 AZL039 % w/w %w/w % w/w % w/w % w/w % w/w % w/w Azelaic Acid 15.00  15.00  15.00 15.00  15.00  15.00  15.00  Caprylic/capric 5.00 10.00  5.00 5.00 5.005.00 10.00  triglyceride Cetostearyl alcohol 0.90 1.00 1.00 1.00 1.001.00 1.00 Glyceryl stearate 0.45 0.50 0.50 0.50 0.50 0.50 0.50Cholesterol 1.00 — — — — 1.00 — Benzoic acid 0.20 — 0.20 0.20 0.20 —Benzyl alcohol 1.00 — 1.00 — — — 1.00 PEG-40 stearate 2.60 2.60 2.602.60 2.60 2.60 Methylcellulose 0.10 0.10 0.10 0.10 0.10 0.10Hydroxypropyl 0.10 — — — — — — methylcellulose Xanthan gum 0.25 0.100.25 0.10 0.25 0.10 0.10 Polysorbate 80 0.90 0.90 0.90 0.90 0.90 0.900.90 EDTA disodium 0.10 — — — — — — dehydrate PEG-400 — — — — 5.00 — —Dimethyl isosorbide 10.00  — — 5.00 — — 5.00 50% phosphotidylcholine —2.80 2.80 — 2.80 — 2.80 in propylene glycol propylene glycol 6.00 5.0010.00  10.00  — — — Sodium hydroxide to pH = to pH = to pH = to pH = topH = to pH = to pH = 4.5 4.5 5.3 4.5 4.5 4.5 5.3 Propellant (butane +8.00 8.00 8.00 8.00 8.00 8.00 8.00 isobutane + propane) Purified waterto 100 to 100 to 100 to 100 to 100 to 100 to 100

Example 11—Compositions with Azalaic Acid with and without DifferentPolymeric Agents

The following foamable vehicles were prepared and the quality of theresultant foam was ascertained.

DCA021 DCA023 DCA023A DCA026 DCA026a Isopropyl 11.00 11.00 myristate MCToil 35.00 35.00 Azelaic acid 20.00 15.00 15.00 15.00 15.00 Propylene30.00 glycol Steareth 2 8.00 8.00 Steareth 21 2.00 2.00 PEG-40 4.00 6.00Stearate Polysorbate 30.00 1.40 2.10 80 Xanthan 0.30 0.27 gum Methocel0.30 0.11 A4M Carboxy 0.50 methyl cellulose Water 19.40 39.50 40.0068.22 65.90 purified Total 100.00 100.00 100.00 100.00 100.00 Propellant8.00 8.00 8.00 8.00 8.00 (propane, isobutene and butane mixtureAppearance: foam quality G-E G-E G-E E E color White White White WhiteWhite odor No odor No odor No odor No odor No odor Microscope CrystalsCrystals Crystals Crystals Crystals

Good to excellent foam formulations were prepared with azelaic acid,surfactant, polymeric agent, and either another oil or propylene glycolwater (and without any foam adjuvant). Reducing the levels of azelaicacid to lower levels eliminated the appearance of crystals (See below).

Surprisingly, it was possible to prepare good to excellent foam afterremoval of the polymeric agent. Thus, the presence of a polymeric agent,is surprisingly not essential for foam quality. Nonetheless, polymericagents may still contribute to and can be significant with respect tofoam and active agent stability.

A3—in Solution Example 12—Azalaic Acid Composition

The following foamable vehicles were prepared and the quality of theresultant foam was ascertained.

DCA022 Azelaic acid 6.00 Propylene glycol 50.00 Polysorbate 80 20.00Xanthan gum 0.30 Methocel A4M 0.30 Water purified 23.40 Total 100.00Propellant ) propane, isobutene 8.00 and butane mixture Appearance: foamquality G-E Color White Odor No odor Microscope No crystals

Lower azaleic acid levels provide a soluble composition. No solids orprecipitates are observed. No crystals were observed at the level ofmicroscopic examination. By no crystals means the ingredients dissolveand it is not a suspension.

Example 13—Compositions with Diethyl Salicylates Azelate (TU-2100)

DCA016 DCA017 DCA016A PPG 15-Stearyl 40.00 40.00 Ether (PPG) Isopropyl40.00 myristate (IPM) TU-2100 10.00 10.00 10.00 Steareth 2 6.00 4.956.00 Steareth 21 1.50 3.00 1.50 Carboxy methyl 0.50 0.50 cellulose Waterpurified 42.00 41.55 42.50 Total 100.00 100.00 100.00 Propellant 8.008.00 8.00 propane, isobutene and butane mixture Appearance: foam qualityG-E G- G-E color White White White odor No odor No odor No odorMicroscope No crystals No crystals No crystals

When medium chain triglycerides were used as the emollient theformulation was poor. However, when they were substituted by PPG or IPMthe foam quality increased substantially. Without being bound by anyparticular theory this may be because the formulations are close tophase reversal and or is due to internal tensions.

Good to excellent foam formulations were prepared with TU-2100, PPG orIPM, surfactant, polymeric agent, and water (and without any foamadjuvant). Surprisingly a good to excellent foam was produced even afterremoval of polymer.

Section B—Non Aqueous B1—Example 14—PEG Based Non Aqueous Formulationswith TU 2100

The following foamable vehicles were prepared and the quality of theresultant foam was ascertained.

DCA014 DCA014A DCA014B TU-2100 10.00 10.00 10.00 PEG 400 87.50 85.0088.00 Steareth 2 2.00 5.00 Klucel EF 0.50 2.00 Total 100.00 100.00100.00 Propellant propane, 8.00 8.00 8.00 isobutene and butane mixtureAppearance: foam quality G-E G-E G-E Color White White White Odor Noodor No odor No odor Microscope No crystals No crystals No crystals

Surprisingly it was possible to make non aqueous PEG based minimal foamcompositions of good to excellent quality with a) active ingredient,PEG, a single surfactant and optionally a polymeric agent and also withb) active ingredient, PEG, and a polymeric agent.

B2—Example 15—PG Based Non Aqueous Formulation with TU 2100 and withAzaleic Acid

The following foamable vehicles were prepared and the quality of theresultant foam was ascertained.

DCA015 DCA020 TU-2100 10.00 Azelaic acid 9.00 PEG 400 Propylene glycol87.50 88.50 Steareth 2 2.00 2.00 Klucel EF 0.50 0.50 Total 100.00 100.00Propellant propane, 8.00 8.00 isobutene and butane mixture Appearance:foam quality G-E G-E color White White odor No odor No odor Microscopecrystals No crystals

Surprisingly it was possible to make non aqueous PG based minimal foamcompositions of good to excellent quality with active ingredient, PG, asingle surfactant and a polymeric agent. Whilst TU 2100 was not solublein the non aqueous PG based composition, azelaic acid was soluble.

What is claimed is:
 1. A foamable composition comprising a carrier and aliquefied or compressed gas propellant, wherein the carrier comprising:(a) about 15% by weight of the carrier of azelaic acid; (b) about 2% toabout 50% by weight of the carrier of a hydrophobic solvent; (c) a polarsolvent; (d) a surface-active agent; (e) a polymeric agent; and (f)water; and wherein the surface-active agent comprises a combination ofat least two surface-active agents and wherein there is a difference ofabout 4 or more units between the HLB values of the at least twosurface-active agents; wherein combined amount of the polymeric agentand the surface-active agent is about 0.05% to about 10% by weight ofthe carrier; and wherein the liquefied or compressed gas propellant ispresent at about 3% to about 25% by weight of the composition.
 2. Thefoamable composition of claim 1, wherein the hydrophobic solventcomprises caprylic/capric triglyceride.
 3. The foamable composition ofclaim 2, wherein caprylic/capric triglyceride is present at about 11% byweight of the carrier.
 4. The foamable composition of claim 1, whereinthe polar solvent comprises dimethyl isosorbide.
 5. The foamablecomposition of claim 4, wherein dimethyl isosorbide is present at about5% by weight of the carrier.
 6. The foamable composition of claim 4,wherein the polar solvent further comprises propylene glycol.
 7. Thefoamable composition of claim 1, wherein the combination comprises atleast one non-ionic surface-active agent having an HLB value of lessthan
 9. 8. The foamable composition of claim 7, wherein the at least onenon-ionic surface-active agent comprises glyceryl stearate.
 9. Thefoamable composition of claim 1, wherein the combination comprises atleast one non-ionic surface-active agent having an HLB value of morethan
 9. 10. The foamable composition of claim 9, wherein the at leastone non-ionic surface-active agent having an HLB value of more than 9comprises PEG-40 stearate and/or Polysorbate
 80. 11. The foamablecomposition of claim 1, wherein the combination comprises at least oneionic surface-active agent.
 12. The foamable composition of claim 1,wherein the polymeric agent is present at about 0.01% to about 5% byweight of the carrier.
 13. The foamable composition of claim 1, whereinthe polymeric agent comprises a naturally-occurring polymeric agentand/or a semi-synthetic polymeric agent.
 14. The foamable composition ofclaim 13, wherein the naturally-occurring polymeric agent comprisesxanthan gum.
 15. The foamable composition of claim 13, wherein thesemi-synthetic polymeric agent comprises methylcellulose.
 16. Thefoamable composition of claim 11, wherein the foamable compositionfurther comprises a foam adjuvant.
 17. The foamable composition of claim16, wherein the foam adjuvant comprises a fatty alcohol having 15 ormore carbons in its carbon chain and/or a fatty acid having 16 or morecarbons in its carbon chain.
 18. The foamable composition of claim 17,wherein the fatty alcohol comprises cetostearyl alcohol.
 19. Thefoamable composition of claim 1, wherein the foamable compositioncomprises less than about 5% by weight of the carrier of a short-chainalcohol.
 20. The foamable composition of claim 1, wherein the foamblecomposition further comprises an anti-perspirant, an anti-static agent,a buffering agent, a bulking agent, a chelating agent, a cleanser, acolorant, a conditioner, a deodorant, a diluent, a dye, an emollient, afragrant, a hair conditioner, a humectant, a pearlescent acid, aperfuming agent, a permeation enhancer, a pH-adjusting agent, apreservative, a protectant, a skin penetrating enhancer, a softener, asolubilizer, a sunscreen, a sun blocking agent, a sunless tanning agent,a viscosity modifier, and/or a vitamin.
 21. The foamable composition ofclaim 1, the pH of the foamable composition is in the range from about4.0 to about 6.0.
 22. The foamable composition of claim 1, wherein thefoamable composition has a shelf-life of at least one year at ambienttemperature.